115 results on '"Chantale Bernatchez"'
Search Results
2. Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target
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Lixia Diao, Esra A. Akbay, Linghua Wang, Won-Chul Lee, Kwok-Kin Wong, Don L. Gibbons, Luisa M. Solis Soto, Ruiping Wang, Stephen G. Swisher, Jing Wang, Runzhe Chen, Roohussaba Khairullah, You Hong Fan, Alexandre Reuben, Mingrui Zhu, Jack A. Roth, Boris Sepesi, Irene Guijarro Munoz, John V. Heymach, Carmen Behrens, Jianhua Zhang, Jacqulyne P. Robichaux, Marcelo V. Negrao, Humam Kadara, Edwin R. Parra, Monique B. Nilsson, Lorenzo Federico, Tatiana Karpinets, Ignacio I. Wistuba, Chantale Bernatchez, Jianjun Zhang, Daniel J. McGrail, S. Patel, Xiuning Le, Ara A. Vaporciyan, Yasir Elamin, Cara Haymaker, Jun Li, and Lauren Averett Byers
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Adenosine ,Lung Neoplasms ,T cell ,Adenocarcinoma of Lung ,Mice ,03 medical and health sciences ,NT5E ,0302 clinical medicine ,Immune system ,Carcinoma, Non-Small-Cell Lung ,Tumor Microenvironment ,Animals ,Medicine ,Cytotoxic T cell ,Lung cancer ,business.industry ,Cancer ,medicine.disease ,Immune checkpoint ,ErbB Receptors ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,business ,medicine.drug - Abstract
Introduction Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood. Methods We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response. Results EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth. Conclusions Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.
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- 2021
3. Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti–PD-1 Refractory Melanoma
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Salah-Eddine Bentebibel, Willem W. Overwijk, Montaser Shaheen, Marc Uemura, Courtney W. Hudgens, Marihella James, Ravi Murthy, Gary C. Doolittle, Robert H.I. Andtbacka, Chantale Bernatchez, Michael A. Davies, S. Chunduru, Douglas B. Johnson, Daniel H. Johnson, Igor Puzanov, Patrick Hwu, Shah Rahimian, Cara Haymaker, Adi Diab, Joseph Markowitz, Denái R. Milton, Michael T. Tetzlaff, Sudhir Agrawal, Nashat Gabrail, and Houssein Safa
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Skin Neoplasms ,Antigen presentation ,Ipilimumab ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Adverse effect ,Immune Checkpoint Inhibitors ,Melanoma ,Aged ,Aged, 80 and over ,business.industry ,Dendritic cell ,Middle Aged ,Gene signature ,medicine.disease ,United States ,Immune checkpoint ,Clinical trial ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti–PD-1– resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. Significance: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone. This article is highlighted in the In This Issue feature, p. 1861
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- 2021
4. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial
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Cheuk Hong Leung, Wayne L. Hofstetter, John V. Heymach, Alexandre Reuben, Myrna C.B. Godoy, Ara A. Vaporciyan, Padmanee Sharma, Yasir Elamin, Neda Kalhor, Robert R. Jenq, Junya Fujimoto, Tina Cascone, Anne S. Tsao, William N. William, Charles Lu, Frank E. Mott, Nadim J. Ajami, Don L. Gibbons, Jack A. Roth, David C. Rice, Luisa M. Solis, Hai T. Tran, Brett W. Carter, Lauren Averett Byers, Andrew Futreal, Lorenzo Federico, Annikka Weissferdt, Garrett L. Walsh, Reza J. Mehran, Chantale Bernatchez, George R. Blumenschein, Jennifer A. Wargo, Heather Lin, Cara Haymaker, Xiuning Le, Jonathan M. Kurie, Mehmet Altan, James P. Allison, Stephen G. Swisher, Edwin R. Parra, Boris Sepesi, Hitoshi Dejima, Frank V. Fossella, Jianjun Zhang, Bonnie S. Glisson, Mara B. Antonoff, Abdul Wadud Khan, Apar Pataer, Alejandro Francisco-Cruz, Ignacio I. Wistuba, Humam Kadara, J. Jack Lee, and Ferdinandos Skoulidis
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Ipilimumab ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Clinical endpoint ,Carcinoma ,Humans ,Medicine ,Lung cancer ,Neoadjuvant therapy ,Aged ,Chemotherapy ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Neoadjuvant Therapy ,Clinical trial ,Nivolumab ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC. Neoadjuvant treatment with nivolumab plus ipilimumab is well tolerated and demonstrates clinical efficacy in patients with early stage lung cancer.
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- 2021
5. Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC
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Erin M. Corsini, Junya Fujimoto, Humam Kadara, Ara A. Vaporciyan, Qi Wang, Jing Wang, Ignacio I. Wistuba, Carmen Behrens, Alexandre Reuben, Stephen G. Swisher, Pierre Olivier Gaudreau, Garrett L. Walsh, Lorenzo Federico, Cara Haymaker, Curtis Gumbs, Emily Roarty, Lixia Diao, Jun Li, Edwin Parra-Cuentas, P. Andrew Futreal, Tatiana Karpinets, John V. Heymach, Hai T. Tran, Boris Sepesi, Daniel J. McGrail, Jianhua Zhang, Kyle G. Mitchell, Annikka Weissferdt, Daniel R. Gomez, Don L. Gibbons, Marcelo V. Negrao, Mara B. Antonoff, Chantale Bernatchez, Latasha Little, Roohussaba Khairullah, Tina Cascone, Jianjun Zhang, and Arlene M. Correa
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,medicine.medical_treatment ,CD8-Positive T-Lymphocytes ,Article ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,parasitic diseases ,Tumor Microenvironment ,medicine ,Humans ,Cytotoxic T cell ,B cell ,CD20 ,B-Lymphocytes ,Chemotherapy ,biology ,medicine.diagnostic_test ,business.industry ,Neoadjuvant Therapy ,Immune checkpoint ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,business ,Immunologic Memory ,Memory T cell ,CD8 - Abstract
Introduction The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade. Methods Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73). Results NCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3− tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery. Conclusions Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.
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- 2021
6. Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy
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Joseph Celestino, Cara Haymaker, Chantale Bernatchez, Marie Andrée Forget, Patrick Hwu, Donastas Sakellariou-Thompson, Emily Hinchcliff, and Amir A. Jazaeri
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Cytotoxicity, Immunologic ,Cancer Research ,medicine.medical_treatment ,CD3 ,Immunology ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Article ,Flow cytometry ,Cell therapy ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,Ovarian Neoplasms ,Salvage Therapy ,Chemotherapy ,medicine.diagnostic_test ,biology ,business.industry ,Tumor-infiltrating lymphocytes ,ELISPOT ,hemic and immune systems ,Chemoradiotherapy ,Immunotherapy ,Prognosis ,medicine.disease ,Cystadenocarcinoma, Serous ,Oncology ,biology.protein ,Cancer research ,Female ,business ,Ovarian cancer ,Follow-Up Studies ,030215 immunology - Abstract
BACKGROUND: Immunotherapy has become a powerful treatment option for several solid tumor types. The presence of tumor-infiltrating lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method. METHODS: TIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT. RESULTS: Ovarian cancer is highly infiltrated with CD8(+) TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 10(6) cells in 2–3 weeks without over differentiation. In addition, the CD8(+) TIL grown with this method showed HLA-restricted tumor recognition. CONCLUSIONS: These results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-tumor TIL in a short time and consistent manner.
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- 2019
7. 962 Integrative immunomics highlight the immunomodulatory impact of neoadjuvant chemotherapy and immune-based treatments in resected non-small-cell lung cancer
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Frank Rojas, Marcelo V. Negrao, Timothy P. Heffernan, Alexandre Reuben, Younghee Lee, Humam Kadara, Jianjun Zhang, Cheuk Hong Leung, Annikka Weissferdt, Christopher A. Bristow, Stephen G. Swisher, Lorenzo Federico, Apar Pataer, John V. Heymach, Tina Cascone, Hitoshi Dejima, Ara A. Vaporciyan, Alejandro Francisco-Cruz, Edwin R. Parra, Ignacio I. Wistuba, Boris Sepesi, Luisa M. Solis, Chantale Bernatchez, Stephanie Schmidt, William N. William, Don L. Gibbons, Heather Lin, Jack Lee, Haiping Guo, Monika Pradhan, and Cara Haymaker
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Pharmacology ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,T cell ,Immunology ,FOXP3 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunosuppression ,medicine.disease ,medicine.anatomical_structure ,Immune system ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,IL-2 receptor ,Nivolumab ,Lung cancer ,business ,CD8 ,RC254-282 - Abstract
BackgroundHow neoadjuvant chemo-immunotherapy modulates tumor immune composition and response is not completely understood. We interrogate immunomodulation of neoadjuvant platinum-based chemotherapy (C), nivolumab (N), and N-plus-C (NC) and their connections to therapeutic efficacy in resected non-small cell lung cancer (NSCLC) by integrating immunomic data from the ImmunogenomiC PrOfiling of NSCLC (ICON) study and NEOSTAR trial cohorts.MethodsIn NEOSTAR (NCT03158129), patients with stage I-IIIA (single N2) resectable NSCLC (AJCC7th) received N (3 mg/kg IV, D1,15,29); patients with stage IB(≥4cm)-IIIA (single N2) resectable NSCLC received NC (N 360 mg IV plus C, D1,22,43 for 3 cycles, every 3 weeks) before surgery; major pathologic response (MPR) was the primary endpoint. In ICON, patients with stage IB(≥4cm)-IIIA resectable NSCLC received C before surgery. Surgically resected tumor samples underwent immune profiling via flow cytometry (n=16,13,9 for C,N,NC), immunohistochemistry (IHC;n=0,18,14), and multiplexed immunofluorescence (mIF;n=28,16,10). Treatment-associated immunomodulation and associations with therapeutic efficacy were analyzed using: 1) a shared nearest neighbors-based network we developed linking measurements across datasets; 2) MetaCyto, a specialized cytometry analysis method for identifying cell subsets by clustering.ResultsWe holistically explored the immunomic data by integration across cohorts. Through hierarchical regression of the integrated data, we determined the overall effect of a given treatment controlling for the presence or absence of the other treatment.We examined C’s effects across all cohorts controlling for N. Across all patients, regardless of MPR, C is associated with immunosuppression, increasing PD1+ T cell (CD45+CD3+) populations: regulatory (CD4+CD25+FOXP3+), helper (CD4+), and effector (CD8+) (effect size(ES):1.48,1.61,1.26;qConversely, we examined N’s effects across all cohorts controlling for C. Across all patients, regardless of MPR, N is associated with immune activation, increasing ICOS+ T cell populations: regulatory, helper, and effector (ES:1.29,1.29,1.47;qConclusionsWe report the first integrated examination of the immunomodulatory effect of neoadjuvant C and N. C is associated with immunosuppression while N with immune activation; together, N appears to lessen C’s suppressive effects. Incorporation of transcriptomics into this integrated network of flow cytometry, mIF, and IHC immune profiling data is ongoing to augment translational insights for neoadjuvant chemo/immunotherapies.
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- 2021
8. 172 Overcoming immunosuppressive TGF-β signaling in human ovarian cancer-derived tumor infiltrating lymphocytes via non-viral CRISPR engineering
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Donastas Sakellariou-Thompson, Marie-Andree Forget, Sanjay Kumar, Yunfei Wang, Amir A. Jazaeri, Christopher Reyes, Chantale Bernatchez, Samantha M. Fix, Rafet Basar, Patrick Hwu, Larissa A. Meyer, and Ana Lucia Dominguez
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Pharmacology ,Cancer Research ,business.industry ,Tumor-infiltrating lymphocytes ,Melanoma ,medicine.medical_treatment ,Immunology ,T-cell receptor ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,medicine.disease ,Helsinki declaration ,Cytokine ,Oncology ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,Medicine ,business ,RC254-282 ,Cancer immunology - Abstract
BackgroundOur ongoing clinical trial for the treatment of melanoma with TGF-β-resistant tumor-infiltrating lymphocytes (TIL) [TGF-β dominant negative receptor 2 (TGFβDNR2) transduced-TIL] has yielded long-term responses in checkpoint refractory patients (NCT01955460). Building on this success, we sought to extend the impact of TGF-β–resistant TIL therapy to additional cancers while optimizing a non-viral alternative to transduction with a TGFβDNR2. Ovarian cancer (OvCa), which is characterized by an abundance of TGF-β, a dysfunctional immune infiltrate, and a paucity of novel treatment options, is an ideal candidate for TGF-β–resistant TIL therapy. Here, we present an optimized and clinically-scalable method for CRISPR/Cas9-mediated deletion of the TGF-β receptor (TGFBR2) in OvCa TIL.MethodsOvCa TIL were generated from tumor fragments1 and subjected to CRISPR-mediated knockout of TGFBR2 before going through a rapid expansion protocol. Resistance of TGFBR2-knockout TIL to TGF-β signaling was evaluated via quantification of downstream SMAD-2/-3 phosphorylation, global transcriptional changes upon TGF-β exposure, and cytokine release following TCR stimulation in the presence of TGF-β. The impact of CRISPR modification on TIL expansion and TCR clonal diversity was evaluated. Finally, the risk of off-target CRISPR activity throughout the genome was evaluated using Target Enriched GUIDE-seq (TEG-seq)2 followed by next generation sequencing (NGS) validation of putative off-target sites.ResultsUsing five TGFBR2-directed guide RNAs (gRNAs), we achieved gene disruption efficiencies ranging from 48%–90%, which correlated inversely with the degree of SMAD phosphorylation after TGF-β exposure (r=-0.9440, p=0.0158, n=4 donors) (figure 1A-C). TGF-β exposure induced a strong transcriptional response in wild-type TIL but had little to no effect on TGFBR2-knockout TIL (figure 2). TGFBR2-knockout TIL functioned well in the presence of exogenous TGF-β as evidenced by equally strong secretion of pro-inflammatory cytokines in the presence and absence of TGF-β (figure 3). CRISPR-modification did not hamper the ex vivo expansion efficiency nor the TCR clonal diversity of expanded OvCa TIL (figure 4). Using TEG-seq, we identified ≤5 low-probability off-target sites for gRNA-#3 and gRNA-#4, each of which were attributed to background sequencing artifacts upon further validation by NGS of specific amplicons (figure 5).Abstract 172 Figure 1(A) Genomic-level TGFBR2 knockout efficiency using 5 different gRNAs as evidenced by NGS of specific amplicons (n=1 TIL donor). (B) SMAD-2 and SMAD-3 phosphorylation in TGFBR2 knockout TIL vs. control TIL after 30 min exposure to TGF-β1. The left panel shows representative histograms of phospho-SMAD staining, and the right panel shows quantification of cells positive for phospho-SMAD-2/-3 after TGF-β exposure (n=4 TIL donors). The statistical significance of each experimental condition compared to the non-transfected control is shown. (C) Inverse correlation of TGFBR2 knockout efficiency and TGF-β-mediated SMAD phosphorylation.Abstract 172 Figure 2Top 100 differentially expressed genes in non-transfected (WT) TIL exposed to TGF-β. TGFBR2 knockout (KO) TIL display minimal gene expression changes upon TGF-β exposure (n=3 technical replicates).Abstract 172 Figure 3TIL were collected after 14 days of expansion and re-stimulated with 300 ng/mL plate-bound anti-CD3 in the presence of 3000 IU/mL IL2 and 10 ng/mL human TGF-β1 or vehicle. Cell culture supernatant was collected after 72 hrs of stimulation and assayed for the presence of 10 proinflammatory cytokines (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α). For TIL with intact TGFBR2 (non-transfected and Cas9 mock transfected TIL), the production of many pro-inflammatory cytokines decreased significantly in the presence of TGF-β. Conversely, TGFBR2 knockout TIL (generated using gRNA #3 or gRNA #4) retain cytokine secretion in the presence of TGF-β. IL-12p70 was below the limit of detection in this assay and is therefore not presented.Abstract 172 Figure 4(A) Control and CRISPR-modified OvCa TIL expand with equal efficiency during a 14-day rapid expansion protocol. Fold expansions ranging from 1000× - 3000× were observed across 4 independent patient samples. (B) The TCR clonal diversity of TIL after 14-day expansion was assessed by TCRB sequencing. Productive Simpson Clonality was equivalent in CRISPR-modified TIL compared to control TIL samples.Abstract 172 Figure 5TEG-seq revealed 3 putative off-target sites for gRNA #3 and 5 putative off-target sites for gRNA #4. The aligned sequences show similarities and differences between the gRNA sequence and the reference genome site. Dots represent exact matches in the reference genome compared to the gRNA sequence. Dashes represent missing bases, lower-case letters represent extra bases, and upper-case letters represent a base mismatch. Validation by NGS of specific amplicons confirmed the presence of TEG-seq Tag integration and large indels at the on-target cleavage sites for gRNA #3 and #4, indicating successful Cas9 editing and Tag integration in our experiment. NGS validation revealed that all putative low probability off-target sites were background artifacts as evidenced by the lack of Tag identification and lack of large indels.ConclusionsCRISPR/Cas9-mediated knockout of TGFBR2 is feasible and efficient in patient-derived OvCa TIL using clinically-scalable methods that yield little to no evidence of off-target activity. This study lays the groundwork for clinical translation of CRISPR-modified, TGF-β-resistant TIL for OvCa treatment, which will not only provide a novel immunotherapy for OvCa patients but also a platform for engineering more potent TIL therapies in general.ReferencesSakellariou-Thompson D, Forget MA, Hinchcliff E, Celestino J, Hwu P, Jazaeri AA, et al. Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy. Cancer Immunology, Immunotherapy: CII 2019;68(11):1747–57.Tang PZ, Ding B, Peng L, Mozhayskiy V, Potter J, Chesnut JD. TEG-seq: an ion torrent-adapted NGS workflow for in cellulo mapping of CRISPR specificity. Bio Techniques 2018;65(5):259–67.Ethics ApprovalAll procedures performed were in accordance with the 1975 Helsinki declaration. Ethical approval and tissue from surgical resections used to expand TIL were both obtained under protocols (PA16-0912 and LAB02-188) approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center. Written informed consent was obtained from all individual participants included in the study for their specimens and data to be used in research and for publication.
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- 2021
9. Identification of MicroRNA–mRNA Networks in Melanoma and Their Association with PD-1 Checkpoint Blockade Outcomes
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Michael A. Davies, Miles C. Andrews, Russell G. Witt, Scott E. Woodman, Rodabe N. Amaria, Jeffrey E. Gershenwald, Khalida Wani, Lauren E. Haydu, Anik Banerjee, Chantale Bernatchez, Robert Sloane, Elizabeth M. Burton, Jennifer A. Wargo, Nadim J. Ajami, Jennifer L. McQuade, Emily Z. Keung, Julie M. Simon, Merrick I. Ross, Linghua Wang, Hussein Abdul-Hassan Tawbi, Michael G. White, Guangchun Han, and Alexander J. Lazar
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Cancer Research ,microRNA ,business.industry ,Melanoma ,Cell ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,immune checkpoint blockade ,Malignancy ,medicine.disease ,Article ,Blockade ,Transcriptome ,medicine.anatomical_structure ,Immune system ,Oncology ,Gene expression ,medicine ,Cancer research ,melanoma ,business ,RC254-282 - Abstract
Simple Summary We conducted a network analysis of microRNA–mRNA associations in melanoma tissue and cell lines to identify the microRNAs central to melanoma biology and their associated gene expression profiles. Further, we evaluated expression of these microRNAs in melanoma patient biopsies and found that increased expression of miR-100-5p and miR-125b-5p were associated with improved outcomes with anti-PD-1 immunotherapy. Further investigation of these microRNAs as biomarkers and potential targets to improve immunotherapy response in melanoma is warranted. Abstract Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and there is an urgent need to understand and mitigate mechanisms of resistance. MicroRNAs are key post-transcriptional regulators of gene expression that regulate many aspects of cancer biology, including immune evasion. We used network analysis to define two core microRNA–mRNA networks in melanoma tissues and cell lines corresponding to ‘MITF-low’ and ‘Keratin’ transcriptomic subsets of melanoma. We then evaluated expression of these core microRNAs in pre-PD-1-inhibitor-treated melanoma patients and observed that higher expression of miR-100-5p and miR-125b-5p were associated with significantly improved overall survival. These findings suggest that miR-100-5p and 125b-5p are potential markers of response to PD-1 inhibitors, and further evaluation of these microRNA–mRNA interactions may yield further insight into melanoma resistance to PD-1 inhibitors.
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- 2021
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10. Challenges and next steps in the advancement of immunotherapy: summary of the 2018 and 2020 National Cancer Institute workshops on cell-based immunotherapy for solid tumors
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Nirali Shah, Lili Yang, Kasia Bourcier, Antoni Ribas, Pawel Kalinski, Ke Liu, Phil Greenberg, Carl June, Marcela Maus, Steven Rosenberg, Madhav Dhodapkar, Irina Tiper, Chantale Bernatchez, Michael Hudecek, Stanley Riddell, Stephen Gottschalk, Crystal Mackall, Lisa Butterfield, Greg Delgoffe, Michael Nishimura, Terry Fry, Marc S. Ernstoff, Christopher Klebanoff, Elad Sharon, Malcolm Brenner, Cliona Rooney, Christine Brown, Marc S Ernstoff, Tonya Webb, Magdalena Thurin, Wendell Lim, David Stroncek, Catherine Bollard, Helen Chen, Cameron Turtle, Christian Hinrichs, Laura K Fogli, Rosemarie Aurigemma, Connie L Sommers, Steven Albelda, Renier Brentjens, Yvonne Chen, Laronna Colbert, Kenneth Cornetta, Jason Cristofaro, Thomas Finn, Laura K Fogli Hunter, Alyssa Galaro, Ananda Goldrath, Ray Harris, Lori Henderson, Yuxia Jia, Dan Kaufman, Bruce Levine, Lawrence Lum, Samantha Maragh, Alex Marson, Raj Puri, Jake Reder, Isabelle Riviere, Kole Roybal, Rachelle Salomon, Tal Salz, Barbra Sasu, Andrea Schietinger, Connie L. Sommers, Minkyung Song, Fyodor Urnov, Anthony Welch, Travis Young, and Jason Yovandich
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0301 basic medicine ,lymphocytes ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Tumor target ,Cell- and Tissue-Based Therapy ,receptors ,adoptive ,History, 21st Century ,Education ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,medicine ,Immunology and Allergy ,Humans ,Medical physics ,RC254-282 ,T-lymphocytes ,Pharmacology ,Tumor microenvironment ,Immune Cell Therapies and Immune Cell Engineering ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,Immunotherapy ,tumor-infiltrating ,medicine.disease ,National Cancer Institute (U.S.) ,United States ,Clinical trial ,Data sharing ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cell based immunotherapy ,chimeric antigen ,Molecular Medicine ,cell therapy ,business - Abstract
Cell-based immunotherapies have had remarkable success in the clinic, specifically in the treatment of hematologic malignancies. However, these strategies have had limited efficacy in patients with solid tumors. To better understand the challenges involved, the National Cancer Institute (NCI) convened an initial workshop with immuno-oncology thought leaders in December 2018 and a follow-up workshop in December 2020. The goals of the NCI workshops on cell-based immunotherapy for solid tumors were to discuss the current state of the field of cell-based immunotherapy, obtain insights into critical knowledge gaps, and identify ways in which NCI could facilitate progress. At both meetings, subjects emphasized four main types of challenges in further developing cell-based immunotherapy for patients with solid tumors: scientific, technical, clinical, and regulatory. The scientific barriers include selecting appropriate targets, ensuring adequate trafficking of cell therapy products to tumor sites, overcoming the immunosuppressive tumor microenvironment, and identifying appropriate models for these investigations. While mouse models may provide some useful data, the majority of those that are commonly used are immunodeficient and unable to fully recapitulate the immune response in patients. There is therefore a need for enhanced support of small early-phase human clinical studies, preferably with adaptive trial designs, to provide proof of concept for novel cell therapy approaches. Furthermore, the requirements for manufacturing, shipping, and distributing cell-based therapies present technical challenges and regulatory questions, which many research institutions are not equipped to address. Overall, workshop subjects identified key areas where NCI support might help the research community in driving forward innovation and clinical utility: 1) provide focused research support on topics such as tumor target selection, immune cell fitness and persistence, cell trafficking, and the immunosuppressive tumor microenvironment; 2) support the rapid translation of preclinical findings into proof of concept clinical testing, harmonize clinical trial regimens, and facilitate early trial data sharing (including negative results); 3) expand manufacturing support for cell therapies, including vectors and reagents, and provide training programs for technical staff; and 4) develop and share standard operating procedures for cell handling and analytical assays, and work with the Food and Drug Administration to harmonize product characterization specifications.
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- 2021
11. Neoantigen vaccination induces clinical and immunologic responses in non-small cell lung cancer patients harboring EGFR mutations
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Zou Qingwei, Ling Han, William K. Decker, Chong Huo, Nikita Kotlov, Michael A. Davies, Cassian Yee, David H. Hawke, Kyle R. Jackson, Gregory Lizée, Caixia Chen, Shuo Zhou, Arjun S. Katailiha, Zhenglu Wang, Deng Ligang, Chantale Bernatchez, Amjad H. Talukder, Wang Yaling, Yulun Chiu, Minying Zhang, Natalia Miheecheva, Felix Frenkel, Matthew Stair, Yan Zhang, Weihong Feng, Jason Roszik, Xueming Du, Patrick Hwu, Aleksander Bagaev, Marie Andrée Forget, Sherille D. Bradley, Roland L. Bassett, Viktor Svekolkin, Ataullakhanov Ravshan I, Fenge Li, and Heather M. Sonnemann
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,T cell ,medicine.medical_treatment ,EGFR ,tumor regression ,Immunology ,Context (language use) ,03 medical and health sciences ,T790M ,0302 clinical medicine ,Immune system ,Internal medicine ,medicine ,Immunology and Allergy ,Lung cancer ,RC254-282 ,non-small cell lung cancer ,EGFR inhibitors ,neoantigen vaccine ,Pharmacology ,Clinical/Translational Cancer Immunotherapy ,Chemotherapy ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,EGFR inhibitor ,030104 developmental biology ,medicine.anatomical_structure ,Tolerability ,030220 oncology & carcinogenesis ,Molecular Medicine ,business - Abstract
BackgroundNeoantigen (NeoAg) peptides displayed at the tumor cell surface by human leukocyte antigen molecules show exquisite tumor specificity and can elicit T cell mediated tumor rejection. However, few NeoAgs are predicted to be shared between patients, and none to date have demonstrated therapeutic value in the context of vaccination.MethodsWe report here a phase I trial of personalized NeoAg peptide vaccination (PPV) of 24 stage III/IV non-small cell lung cancer (NSCLC) patients who had previously progressed following multiple conventional therapies, including surgery, radiation, chemotherapy, and tyrosine kinase inhibitors (TKIs). Primary endpoints of the trial evaluated feasibility, tolerability, and safety of the personalized vaccination approach, and secondary trial endpoints assessed tumor-specific immune reactivity and clinical responses. Of the 16 patients with epidermal growth factor receptor (EGFR) mutations, nine continued TKI therapy concurrent with PPV and seven patients received PPV alone.ResultsOut of 29 patients enrolled in the trial, 24 were immunized with personalized NeoAg peptides. Aside from transient rash, fatigue and/or fever observed in three patients, no other treatment-related adverse events were observed. Median progression-free survival and overall survival of the 24 vaccinated patients were 6.0 and 8.9 months, respectively. Within 3–4 months following initiation of PPV, seven RECIST-based objective clinical responses including one complete response were observed. Notably, all seven clinical responders had EGFR-mutated tumors, including four patients that had continued TKI therapy concurrently with PPV. Immune monitoring showed that five of the seven responding patients demonstrated vaccine-induced T cell responses against EGFR NeoAg peptides. Furthermore, two highly shared EGFR mutations (L858R and T790M) were shown to be immunogenic in four of the responding patients, all of whom demonstrated increases in peripheral blood neoantigen-specific CD8+ T cell frequencies during the course of PPV.ConclusionsThese results show that personalized NeoAg vaccination is feasible and safe for advanced-stage NSCLC patients. The clinical and immune responses observed following PPV suggest that EGFR mutations constitute shared, immunogenic neoantigens with promising immunotherapeutic potential for large subsets of NSCLC patients. Furthermore, PPV with concurrent EGFR inhibitor therapy was well tolerated and may have contributed to the induction of PPV-induced T cell responses.
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- 2021
12. Randomized phase II trial of lymphodepletion plus adoptive cell transfer of tumor-infiltrating lymphocytes, with or without dendritic cell vaccination, in patients with metastatic melanoma
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Laszlo Radvanyi, Cara Haymaker, Sapna Pradyuman Patel, Adi Diab, Elizabeth J. Shpall, Roland L. Bassett, Rodabe N. Amaria, Chantal Saberian, Patrick Hwu, Hussein Abdul-Hassan Tawbi, Sapna R. Parshottam, Marie Andrée Forget, Amer Najjar, Jennifer L. McQuade, Michael A. Davies, Gregory Lizée, Chantale Bernatchez, Victor G. Prieto, Cassian Yee, Silvana de Castro Faria, Isabella C. Glitza, Michael K. Wong, and Enrique Alvarez
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Oncology ,lymphocytes ,Male ,Cancer Research ,Adoptive cell transfer ,Skin Neoplasms ,Time Factors ,T-Lymphocytes ,Immunotherapy, Adoptive ,Clinical endpoint ,Immunology and Allergy ,RC254-282 ,Clinical/Translational Cancer Immunotherapy ,medicine.diagnostic_test ,integumentary system ,Melanoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,hemic and immune systems ,adaptive immunity ,Middle Aged ,Acquired immune system ,Combined Modality Therapy ,Treatment Outcome ,Molecular Medicine ,Female ,Adult ,medicine.medical_specialty ,Adolescent ,Immunology ,chemical and pharmacologic phenomena ,Cancer Vaccines ,Lymphocyte Depletion ,Flow cytometry ,Young Adult ,Lymphocytes, Tumor-Infiltrating ,MART-1 Antigen ,Internal medicine ,medicine ,melanoma ,Humans ,dendritic cells ,neoplasms ,Neoplasm Staging ,Pharmacology ,business.industry ,Tumor-infiltrating lymphocytes ,Dendritic cell ,tumor-infiltrating ,medicine.disease ,vaccination ,business ,CD8 - Abstract
BackgroundThe adoptive transfer of tumor-infiltrating lymphocytes (TIL) has demonstrated robust efficacy in metastatic melanoma patients. Tumor antigen–loaded dendritic cells (DCs) are believed to optimally activate antigen-specific T lymphocytes. We hypothesized that the combined transfer of TIL, containing a melanoma antigen recognized by T cells 1 (MART-1) specific population, with MART-1-pulsed DC will result in enhanced proliferation and prolonged survival of transferred MART-1 specific T cells in vivo ultimately leading to improved clinical responses.DesignWe tested the combination of TIL and DC in a phase II clinical trial of patients with advanced stage IV melanoma. HLA-A0201 patients whose early TIL cultures demonstrated reactivity to MART-1 peptide were randomly assigned to receive TIL alone or TIL +DC pulsed with MART-1 peptide. The primary endpoint was to evaluate the persistence of MART-1 TIL in the two arms. Secondary endpoints were to evaluate clinical response and survival.ResultsTen patients were given TIL alone while eight patients received TIL+DC vaccine. Infused MART-1 reactive CD8+ TIL were tracked in the blood over time by flow cytometry and results show good persistence in both arms, with no difference in the persistence of MART-1 between the two arms. The objective response rate was 30% (3/10) in the TIL arm and 50% (4/8) in the TIL+DC arm. All treatments were well tolerated.ConclusionsThe combination of TIL +DC showed no difference in the persistence of MART-1 TIL compared with TIL therapy alone. Although more patients showed a clinical response to TIL+DC therapy, this study was not powered to resolve differences between groups.Trial registration numberNCT00338377.
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- 2021
13. Pulmonary resection for tissue harvest in adoptive tumor-infiltrating lymphocyte therapy: Safety and feasibility
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Jack A. Roth, David C. Rice, Garrett L. Walsh, Ara A. Vaporciyan, Ravi Rajaram, Rodabe N. Amaria, Cara Haymaker, Erin M. Corsini, Mara B. Antonoff, Reza J. Mehran, Stephen G. Swisher, Wayne L. Hofstetter, Amir A. Jazaeri, Nicolas Zhou, Boris Sepesi, Chantale Bernatchez, Marie-Andree Forget, and Kyle G. Mitchell
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Adult ,Male ,medicine.medical_specialty ,Blood transfusion ,Lung Neoplasms ,medicine.medical_treatment ,Pulmonary Surgical Procedures ,Immunotherapy, Adoptive ,03 medical and health sciences ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,Tumor infiltrating lymphocyte therapy ,medicine ,Thoracoscopy ,Humans ,Prospective Studies ,Melanoma ,Postoperative Care ,medicine.diagnostic_test ,Urinary retention ,business.industry ,Tumor-infiltrating lymphocytes ,General Medicine ,Middle Aged ,Prognosis ,Surgery ,Chest tube ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Feasibility Studies ,030211 gastroenterology & hepatology ,Female ,medicine.symptom ,Pulmonary resection ,business ,Follow-Up Studies - Abstract
Background and objectives Adoptive T-cell therapies (ACTs) using expansion of tumor-infiltrating lymphocyte (TIL) populations are of great interest for advanced malignancies, with promising response rates in trial settings. However, postoperative outcomes following pulmonary TIL harvest have not been widely documented, and surgeons may be hesitant to operate in the setting of widespread disease. Methods Patients who underwent pulmonary TIL harvest were identified, and postoperative outcomes were studied, including pulmonary, cardiovascular, infectious, and wound complications. Results 83 patients met inclusion criteria. Pulmonary TIL harvest was undertaken primarily via a thoracoscopy with a median operative blood loss and duration of 30 ml and 65 min, respectively. The median length of stay was 2 days. Postoperative events were rare, occurring in only five (6%) patients, including two discharged with a chest tube, one discharged with oxygen, one episode of urinary retention, and one blood transfusion. No reoperations occurred. The median time from TIL harvest to ACT infusion was 37 days. Conclusions Pulmonary TIL harvest is safe and feasible, without major postoperative events in our cohort. All patients were able to receive intended ACT infusion without delays. Therefore, thoracic surgeons should actively participate in ongoing ACT trials and aggressively seek to enroll patients on these protocols.
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- 2021
14. Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma
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Young Uk Kim, Marie Andrée Forget, Rahmatu Mansaray, Rene J. Tavera, Arely Wahl, Patrick Hwu, Seth Wardell, Esteban Flores, Dan S. Gombos, Audrey M. Gonzalez, Laszlo Radvanyi, Orenthial J. Fulbright, Christopher Toth, Donastas Sakellariou-Thompson, Rodabe N. Amaria, Renjith Ramachandran, Caitlin Creasy, Cara Haymaker, Sapna Pradyuman Patel, Ankit Bhatta, Chantale Bernatchez, and Shawne T. Thorsen
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Male ,Uveal Neoplasms ,0301 basic medicine ,Interleukin 2 ,Cancer Research ,Skin Neoplasms ,T-Lymphocytes ,T cell ,medicine.medical_treatment ,Immunology ,chemical and pharmacologic phenomena ,Immunotherapy, Adoptive ,Article ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,Melanoma ,Pharmacology ,Tumor-infiltrating lymphocytes ,business.industry ,CD137 ,hemic and immune systems ,Immunotherapy ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,Cancer research ,Interleukin-2 ,Female ,business ,CD8 ,medicine.drug - Abstract
In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy-the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8 TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8CD3 TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in
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- 2018
15. Network for biomarker immunoprofiling for cancer immunotherapy: Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC)
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Minkyung Song, Sean C. Bendall, Melissa D. Bowman, James Lindsay, Diane Marie Del Valle, J. Jack Lee, Cathy Rowe, Gerold Bongers, Jenny Peterson-Klaus, James H. Doroshow, Valerie M. Tatard-Leitman, F. Stephen Hodi, Holden T. Maecker, Chia-Chi Chang, Sacha Gnjatic, David Patton, Srinika Ranasinghe, Ethan Cerami, Lyndsay Harris, Jeffrey S. Abrams, Magdalena Thurin, Stacey J Adam, Ignacio I. Wistuba, Rebecca A. Enos, Helen X. Chen, Margaret M. Mooney, Sylvie Janssens, Robert R. Jenq, Elad Sharon, Howard Streicher, Chantale Bernatchez, Mina Pichavant, Joyce Yu, Stephen M. Hewitt, Catherine J. Wu, Beatriz Sanchez-Espiridion, Xiaole Shirley Liu, Radim Moravec, Ming Tang, and Gheath Alatrash
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,MEDLINE ,Immune monitoring ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Monitoring, Immunologic ,Neoplasms ,medicine ,Biomarkers, Tumor ,Humans ,Medical physics ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,Clinical trial ,030104 developmental biology ,Oncology ,Informatics ,Biomarker (medicine) ,business ,030217 neurology & neurosurgery - Abstract
Purpose: Immunoprofiling to identify biomarkers and integration with clinical trial outcomes are critical to improving immunotherapy approaches for patients with cancer. However, the translational potential of individual studies is often limited by small sample size of trials and the complexity of immuno-oncology biomarkers. Variability in assay performance further limits comparison and interpretation of data across studies and laboratories. Experimental Design: To enable a systematic approach to biomarker identification and correlation with clinical outcome across trials, the Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC) Network was established through support of the Cancer MoonshotSM Initiative of the National Cancer Institute (NCI) and the Partnership for Accelerating Cancer Therapies (PACT) with industry partners via the Foundation for the NIH. Results: The CIMAC-CIDC Network is composed of four academic centers with multidisciplinary expertise in cancer immunotherapy that perform validated and harmonized assays for immunoprofiling and conduct correlative analyses. A data coordinating center (CIDC) provides the computational expertise and informatics platforms for the storage, integration, and analysis of biomarker and clinical data. Conclusions: This overview highlights strategies for assay harmonization to enable cross-trial and cross-site data analysis and describes key elements for establishing a network to enhance immuno-oncology biomarker development. These include an operational infrastructure, validation and harmonization of core immunoprofiling assays, platforms for data ingestion and integration, and access to specimens from clinical trials. Published in the same volume are reports of harmonization for core analyses: whole-exome sequencing, RNA sequencing, cytometry by time of flight, and IHC/immunofluorescence.
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- 2021
16. 311 Phase II trial of lymphodepletion plus adoptive cell transfer with or without dendritic cell vaccination in patients with metastatic melanoma
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Jeniffer McQuade, Rodabe N. Amaria, Hussein Abdul-Hassan Tawbi, Chantal Saberian, Marie Andrée Forget, Gregory Lizée, Michael Davies, Chantale Bernatchez, Patrick Hwu, Roland L. Bassett, Cara Haymaker, Sapna Pradyuman Patel, Adi Diab, Michael K. Wong, Isabella C. Glitza, and Cassian Yee
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0301 basic medicine ,Oncology ,Adoptive cell transfer ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,chemical and pharmacologic phenomena ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,education ,Chemotherapy ,education.field_of_study ,business.industry ,Cancer ,hemic and immune systems ,Immunotherapy ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,CD8 ,Brain metastasis - Abstract
Background Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has shown great benefit in patients with melanoma.1,2 It was suggested that long term tumor immunosurveillance is provided by TIL persisting after transfer. Dendritic cells (DC) are professional antigen presenting cells and have the ability to optimally activate T lymphocytes.3 We hypothesized that the combination of autologous TIL containing a population of HLA-A0201 restricted MART-1 reactive CD8+ TIL with autologous MART-1 antigen-pulsed DCs will result in enhanced proliferation and prolonged survival of the transferred antigen-specific T cells in vivo, thus leading to improved clinical responses. Methods This is a randomized phase II trial of lymphodepleting chemotherapy followed by autologous TILs ± DC vaccine and high dose Interleukin-2 (IL-2) for patients with metastatic melanoma. Patients were randomized to receive TIL alone or TIL + DCs pulsed with MART-1 peptide. The primary objective was to determine whether patients receiving TIL + DCs have sustained persistence of infused T cells compared to patients treated with TIL alone. Secondary endpoints included evaluation of tumor response and survival. Results A total of 18 patients with stage IV melanoma were treated; 89% with stage M1c, including 56% with brain metastasis; 17% had high LDH level. All but one patient were checkpoint naive prior to TIL. Ten patients received TIL alone and eight received TIL + DC. Treatments were well tolerated with no grade 5 adverse events. There were no toxicities conferred by the DC vaccination. The ORR was 63% (5/8) in TIL + DC arm (1 CR, 4 PR) and 40% (4/10) in TIL arm alone (1 CR, 3 PR) (P=0.64). There was no statistically significant difference in survival between the arms. The median progression-free survival (PFS) was 3.6 months in the TIL arm and 7.2 months in the TIL+DC arm, while the median overall survival (OS) was 4.1 years in the TIL arm and 2 years in the TIL+DC arm. Tracking of the infused MART-1 reactive CD8+ T cells in the blood over time by flow cytometry showed no difference in persistence between the two arms. Conclusions ACT with TILs has robust response in checkpoint naive advanced melanoma patients. Despite numerically higher response rate in the TIL+DC arm, due to small patient number there was no statistically significant difference between the arms. Further testing of this approach in a prospective trial post-ICI is warranted. Trial Registration All metastatic melanoma TIL lines were derived from tumor tissue obtained from patients enrolled on the TIL ACT clinical trial [institutional review board (IRB)-approved protocol# 2004-0069, NCT00338377] at The University of Texas MD Anderson Cancer Center. Ethics Approval The United States Food and Drug Administration and the Institutional Review Board at MD Anderson Cancer Center approved the study. This study was conducted according to the principles from the Declaration of Helsinki. Consent All study participants granted a written informed consent prior to treatment initiation. References Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348(6230):62–8. Forget MA, Haymaker C, Hess KR, Meng YJ, Creasy C, Karpinets T, et al. Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome. Clin Cancer Res. 2018;24(18):4416–28. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52.
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- 2020
17. Neutrophil expansion defines an immunoinhibitory peripheral and intratumoral inflammatory milieu in resected non-small cell lung cancer: a descriptive analysis of a prospectively immunoprofiled cohort
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Chantale Bernatchez, Jing Wang, Alexandre Reuben, Hitoshi Dejima, Alejandro Francisco-Cruz, Tina Cascone, Ignacio I. Wistuba, Lorenzo Federico, Don L. Gibbons, Tatiana Karpinets, Boris Sepesi, Stephen G. Swisher, Edwin R. Parra, Marcelo V. Negrao, Jianjun Zhang, Mara B. Antonoff, Kyle G. Mitchell, John V. Heymach, Hai T. Tran, Lixia Diao, Erin M. Corsini, Ara A. Vaporciyan, and Cara Haymaker
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Neutrophils ,Lymphocyte ,medicine.medical_treatment ,GZMB ,immunology ,surgery ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Immunotherapy Biomarkers ,medicine ,Immunology and Allergy ,Humans ,Prospective Studies ,Lung cancer ,RC254-282 ,Pharmacology ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,interferon ,medicine.disease ,Prognosis ,Neutrophilia ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,030220 oncology & carcinogenesis ,oncology ,Absolute neutrophil count ,Molecular Medicine ,Tumor necrosis factor alpha ,Female ,medicine.symptom ,business ,CD8 - Abstract
BackgroundThe biological underpinnings of the prognostic and predictive significance of a relative neutrophilia in patients with non-small lung cancer (NSCLC) are undefined. We sought to comprehensively examine the relationships between circulating and intratumoral neutrophil populations and features of the immune contexture in patients undergoing NSCLC resection.MethodsPreoperative soluble cytokine and angiogenic factors; tumor multiplex immunofluorescence; RNA, whole exome, and T-cell receptor sequencing; and flow cytometry were analyzed for relationships with populations of circulating (from complete blood counts) and intratumoral neutrophils (transcriptional signatures) in a prospectively enrolled resected NSCLC cohort (n=66). In a historical cohort (n=1524), preoperative circulating neutrophil and lymphocyte counts were analyzed for associations with overall survival (OS).ResultsCirculating neutrophil populations were positively correlated with increased tumor burden, and surgical tumor resection was followed by a subsequent reduction in peripheral neutrophil counts. Expansion of the circulating neutrophil compartment was associated with increased levels of pro-granulopoietic (IL-1β, IL-17A, TNFα, IL-6) and TH2-associated (IL-5, IL-13) cytokines. Tumors with high intratumoral neutrophil burden were marked by a blunted T-cell response characterized by reduced expression of cytotoxic T-cell genes (CD8A,CD8B,GZMA,GZMB), decreased CD3+CD8+cell infiltration, and diminished expression of IFNγ-related genes. The associations between increased intratumoral neutrophil burden and reduced CD3+CD8+infiltration persisted after adjustment for tumor size, histology, mutational burden, and PD-L1 expression. In 1524 patients, elevated preoperative circulating neutrophil count was independently associated with worse OS (main effect HR 1.82, 95% CI 1.24 to 2.68, p=0.002).ConclusionsOur findings demonstrate that neutrophil expansion reflects protumorigenic and immunosuppressive processes that manifest as worse OS in patients undergoing NSCLC resection. These results justify further investigation of therapeutic strategies targeting neutrophil-associated immune evasion.
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- 2020
18. Peripheral cytokines are not influenced by the type of surgical approach for non-small cell lung cancer by four weeks postoperatively
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Mara B. Antonoff, Jianjun Zhang, Jing Wang, Alexandre Reuben, Kyle G. Mitchell, Don L. Gibbons, Wayne L. Hofstetter, Garrett L. Walsh, Tina Cascone, Reza J. Mehran, Boris Sepesi, Hai T. Tran, Mayra E. Vasquez, Jack A. Roth, Chantale Bernatchez, Erin M. Corsini, Ara A. Vaporciyan, Cara Haymaker, Stephen G. Swisher, John V. Heymach, Qi Wang, and David C. Rice
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Thoracotomy ,Lung cancer ,Pneumonectomy ,Neoadjuvant therapy ,Retrospective Studies ,Lung cancer surgery ,Surgical approach ,business.industry ,Thoracic Surgery, Video-Assisted ,medicine.disease ,Peripheral ,Surgery ,030104 developmental biology ,Cytokine ,Oncology ,030220 oncology & carcinogenesis ,Cytokines ,business - Abstract
Objectives The influence of surgical approach on systemic inflammatory response and the subsequent oncologic impact for non-small cell lung cancer is debated. We aimed to measure the effects of thoracic surgical approach on peripheral cytokine milieu over time. Methods Patients undergoing primary lung resection without neoadjuvant therapy (2016–2018) were evaluated. A panel of 43 cytokines, angiogenic factors, and inflammatory molecules (CAFs) were evaluated in peripheral blood preoperatively, at 24 -hs and 4-weeks postoperatively. Differences between CAFs in patients undergoing thoracotomy versus video-assisted thoracoscopic surgery (VATS) at all timepoints were assessed using Student’s t-test. Results 76 patients with available peripheral CAF panels met inclusion criteria. Thoracotomy was performed in 53 (70 %) patients while VATS was undertaken in 23 (30 %). Upon examination of known inflammatory CAFs, including IL-1β, IL-6, IL-8, IL-10, IFN-γ, and soluble (s) CD27, no differences were detected at 24 h or 4 weeks postoperatively between surgical groups. Examination of trends over time did not demonstrate any temporal derangements for these CAFs, with return to baseline levels by 4 weeks postoperatively for both groups. Evaluation of soluble (s) checkpoint molecules, including sPD-1, sPD-L1, sTIM-3, and sCTLA-4, did not reveal any differences in the immediate postoperative or long-term recovery period. Conclusions Peripheral immune profiles following pulmonary resection do not appear to differ between VATS and thoracotomy postoperatively. CAF fluctuations are transient and recover rapidly. These results, at the peripheral cytokine level, suggest that the surgical approach for lung cancer is unlikely to alter the effectiveness of novel immune-modulating systemic therapies, although more studies are needed to validate these findings.
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- 2020
19. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy
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Marie Andrée Forget, Barbara Pazdrak, Yared Hailemichael, Meenu Sharma, Patrick Hwu, Cara Haymaker, Adi Diab, Binisha Karki, Ute Hoch, Christina Vianden, Deborah H. Charych, Manisha Singh, Caitlin Creasy, Cristian Coarfa, Michael E. Hurwitz, Salah Eddine Bentebibel, Mario Sznol, Uddalak Bharadwaj, Hiep Khong, Kimal Rajapakshe, Chantale Bernatchez, David J. Tweardy, Jonathan Zalevsky, Murali Addepalli, Srinivas Vennam, Faisal Fa’ak, Willem W. Overwijk, Shixia Huang, Louise M.E. Janssen, Brent C. Chesson, and Laura Maria S. Kahn
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0301 basic medicine ,Cancer therapy ,medicine.medical_treatment ,General Physics and Astronomy ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Polyethylene Glycols ,Cohort Studies ,Mice ,0302 clinical medicine ,Prodrugs ,Lymphocytes ,lcsh:Science ,Receptor ,Melanoma ,Multidisciplinary ,3. Good health ,Cytokine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Monoclonal ,Tumour immunology ,Cytokines ,Drug Therapy, Combination ,Female ,Immunotherapy ,medicine.symptom ,Science ,T cell ,Antibodies, Monoclonal, Humanized ,Article ,General Biochemistry, Genetics and Molecular Biology ,Interferon-gamma ,03 medical and health sciences ,medicine ,Animals ,Humans ,Carcinoma, Renal Cell ,Tumor Necrosis Factor-alpha ,business.industry ,Cancer ,Receptors, Interleukin-2 ,General Chemistry ,medicine.disease ,Ipilimumab ,Blockade ,Mice, Inbred C57BL ,030104 developmental biology ,Mechanism of action ,Cancer research ,Interleukin-2 ,lcsh:Q ,business ,CD8 - Abstract
High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies., Interleukin-2 can induce an anti-tumour response, but is associated with toxicity. Here, the authors demonstrate that an engineered interleukin-2 promotes intratumoral T regulatory cell depletion while enhancing effective anti-tumour CD8+ T cell responses that result in potent tumor suppression.
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- 2020
20. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
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Daniel C. Cho, Harriet M. Kluger, Scott N. Gettinger, Chantale Bernatchez, Christie Fanton, Yijie Liao, Ernesto Iacucci, Mary Tagliaferri, Michael E. Hurwitz, Alison L. Hannah, Scott S. Tykodi, Cara Haymaker, Salah Eddine Bentebibel, Adi Diab, Ute Hoch, Jonathan Zalevsky, Vassiliki A. Papadimitrakopoulou, Sandra Aung, Mario Sznol, Ahsan Naqi Rizwan, Patrick Hwu, Nizar M. Tannir, and Brendan D. Curti
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Polyethylene Glycols ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Lymphocytes, Tumor-Infiltrating ,Renal cell carcinoma ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lymphocyte Count ,Adverse effect ,Carcinoma, Renal Cell ,Immune Checkpoint Inhibitors ,Melanoma ,Aged ,business.industry ,Metabolic acidosis ,Immunotherapy ,Middle Aged ,medicine.disease ,Rash ,Kidney Neoplasms ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Nivolumab ,Treatment Outcome ,030220 oncology & carcinogenesis ,Interleukin-2 ,Female ,medicine.symptom ,business ,CD8 - Abstract
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non–small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. Significance: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade. See related commentary by Rouanne et al., p. 1097. This article is highlighted in the In This Issue feature, p. 1079
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- 2019
21. 174 Combined IL-2, agonistic CD3 and 4–1BB stimulation preserve clonotype hierarchy in propagated non-small cell lung cancer tumor-infiltrating lymphocytes
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John V. Heymach, Boris Sepesi, Alexandre Reuben, Chi-Wan Chow, Ara A. Vaporciyan, Roohussaba Khairullah, Marie Andrée Forget, Ignacio I. Wistuba, Peixin Jiang, Marcelo V. Negrao, Parin Shah, Annika Weissferdt, Anirban Maitra, Junya Fujimoto, Lorenzo Federico, Don L. Gibbons, Tina Cascone, Chantale Bernatchez, Meredith Frank, Cara Haymaker, Jack A. Roth, Jianjun Zhang, Yan Long, Daniel J. McGrail, S.H. Lin, and Kyle G. Mitchell
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Pharmacology ,Cancer Research ,Adoptive cell transfer ,Tumor-infiltrating lymphocytes ,business.industry ,medicine.medical_treatment ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,Immunotherapy ,Pembrolizumab ,medicine.disease ,Oncology ,Docetaxel ,medicine ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,Nivolumab ,Lung cancer ,business ,RC254-282 ,medicine.drug - Abstract
BackgroundWhile immune checkpoint blockade is regarded as standard of care for treatment of non-small cell lung cancer (NSCLC), up to 50% of patients with metastatic NSCLC do not achieve an optimal response.1–3 Previous work by our group and others in adoptive cell therapy (ACT) of metastatic melanoma (MM) has shown that infusion of a CD8+-rich TIL product significantly improved clinical outcomes, yet traditional IL-2 expansion methods have resulted in a predominantly CD4+ NSCLC TIL expansion product.7–12 This preclinical study explores the feasibility of producing a tumor-specific, CD8+-enriched NSCLC TIL product for ACT with an improved culture method.MethodsTIL from resected NSCLC tumors were cultured using 1) the traditional method using IL-2 alone in 24-well plates (TIL 1.0) or 2) IL-2 in combination with agonistic antibodies against CD3 and 4-1BB (Urelumab) in a G-Rex flask (TIL 3.0). Expanded TIL were phenotyped using flow cytometry for CD4 and CD8 subset assessment and the CDR3-beta variable region of the T-cell receptor (TCR) involved in antigen binding was sequenced to assess the T-cell repertoire.ResultsIn a shorter manufacturing time (median of 14 days vs 27.5 days), TIL 3.0 expanded on average 5.3-times more NSCLC TIL (95% CI= 4.3–6.2, pConclusionsThis study reports the feasibility of using the TIL 3.0 methodology to robustly expand a CD8+ T-cell repertoire which maintains the respective clonal hierarchy in NSCLC tumors and enriches for putative tumor-specific TIL clones. The robustness and speed of the new process may facilitate testing and implementing effective TIL ACT in NSCLC.ReferencesGaron EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372(21):2018–28.Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(17):1627–39.Gettinger S, Horn L, Jackman D, Spigel D, Antonia S, Hellmann M, et al. Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: Results from the CA209–003 Study. J Clin Oncol 2018;36(17):1675–84.Melioli G, Ratto G, Guastella M, Meta M, Biassoni R, Semino C, et al. Isolation and in vitro expansion of lymphocytes infiltrating non-small cell lung carcinoma: functional and molecular characterisation for their use in adoptive immunotherapy. Eur J Cancer 1994;30A(1):97–102.McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351(6280):1463–9.Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011;17(13):4550–7.Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, et al. Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 2010;16(9):2646–55.Pilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, et al. Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother 2012;35(8):615–20.Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, et al. Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients. Clinical Cancer Research 2012;18(24):6758–70.Forget MA, Haymaker C, Hess KR, Meng YJ, Creasy C, Karpinets T, et al. Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome. Clin Cancer Res 2018;24(18):4416–28.Ben-Avi R, Farhi R, Ben-Nun A, Gorodner M, Greenberg E, Markel G, et al. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol Immunother 2018;67(8):1221–30.Ma Y, Ou J, Lin T, Chen L, Wang J, Qiao D, et al. Phenotypic analysis of tumor-infiltrating lymphocytes from non-small cell lung cancer and their potential application for adoptive cell therapy. Immunopharmacol Immunotoxicol 2020;42(4):319–29Ethics ApprovalThis study was performed on NSCLC tumor tissue resected from 16 patients enrolled, following informed consent, in the ImmunogenomiC prOfiling of early-stage NSCLC (ICON) project. This study was approved by the University of Texas MD Anderson Cancer Center‘s Institutional Review Board (protocol number PA15-1112_MODCR001).
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- 2021
22. The Effect of Topoisomerase I Inhibitors on the Efficacy of T-Cell-Based Cancer Immunotherapy
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Marie-Andree Forget, Min Zhang, Rina M. Mbofung, Ashish Kalra, Timothy P. Heffernan, R. Eric Davis, Trang N. Tieu, Weiyi Peng, Florian L. Muller, Seram Devi, Cara Haymaker, Patrick Hwu, Chantale Bernatchez, Chengwen Liu, Soraya Zorro Manrique, Anil K. Sood, Chunyu Xu, Leila Williams, Nikunj Satani, Jodi A. McKenzie, Shruti Malu, Rodabe N. Amaria, Sunila Pradeep, Yuan Chen, Emily Ashkin, Lu Huang, Jason Roszik, and Jianhua Hu
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0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,T cell ,Irinotecan ,Immunotherapy, Adoptive ,Mice ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Cancer immunotherapy ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Cytotoxicity ,Melanoma ,Tumor microenvironment ,biology ,business.industry ,Topoisomerase ,Articles ,Immunotherapy ,medicine.disease ,Combined Modality Therapy ,Xenograft Model Antitumor Assays ,3. Good health ,Mice, Inbred C57BL ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,Topotecan ,Topoisomerase I Inhibitors ,business ,T-Lymphocytes, Cytotoxic ,medicine.drug - Abstract
Background Immunotherapy has increasingly become a staple in cancer treatment. However, substantial limitations in the durability of response highlight the need for more rational therapeutic combinations. The aim of this study is to investigate how to make tumor cells more sensitive to T-cell-based cancer immunotherapy. Methods Two pairs of melanoma patient-derived tumor cell lines and their autologous tumor-infiltrating lymphocytes were utilized in a high-throughput screen of 850 compounds to identify bioactive agents that could be used in combinatorial strategies to improve T-cell-mediated killing of tumor cells. RNAi, overexpression, and gene expression analyses were utilized to identify the mechanism underlying the effect of Topoisomerase I (Top1) inhibitors on T-cell-mediated killing. Using a syngeneic mouse model (n = 5 per group), the antitumor efficacy of the combination of a clinically relevant Top1 inhibitor, liposomal irinotecan (MM-398), with immune checkpoint inhibitors was also assessed. All statistical tests were two-sided. Results We found that Top1 inhibitors increased the sensitivity of patient-derived melanoma cell lines (n = 7) to T-cell-mediated cytotoxicity (P < .001, Dunnett’s test). This enhancement is mediated by TP53INP1, whose overexpression increased the susceptibility of melanoma cell lines to T-cell cytotoxicity (2549 cell line: P = .009, unpaired t test), whereas its knockdown impeded T-cell killing of Top1 inhibitor–treated melanoma cells (2549 cell line: P < .001, unpaired t test). In vivo, greater tumor control was achieved with MM-398 in combination with α-PD-L1 or α-PD1 (P < .001, Tukey’s test). Prolonged survival was also observed in tumor-bearing mice treated with MM-398 in combination with α-PD-L1 (P = .002, log-rank test) or α-PD1 (P = .008, log-rank test). Conclusions We demonstrated that Top1 inhibitors can improve the antitumor efficacy of cancer immunotherapy, thus providing the basis for developing novel strategies using Top1 inhibitors to augment the efficacy of immunotherapy.
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- 2017
23. Abstract 619: Integrated multi-platform profiling of early-stage non-small cell lung cancer identifies relationship between disease recurrence and decreased native immune response in treatment-naïve resected NSCLC
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Cara Haymaker, Neal Akhave, Andrew Futreal, Lorenzo Federico, Chantale Bernatchez, Jianjun Zhang, Christopher A. Bristow, Marcelo V. Negrao, Tina Cascone, Ignacio I. Wistuba, Boris Sepesi, Carmen Behrens, Younghee Lee, Don L. Gibbons, Lauren Averett Byers, Annikka Weissferdt, Lixia Diao, Marie-Andree Forget, Stephanie Schmidt, Ara A. Vaporciyan, Beatriz Sanchez-Espiridion, John V. Heymach, Alexandre Reuben, Jing Wang, Junya Fujimoto, Daniel J. McGrail, Jun Li, S.H. Lin, and Jianhua Zhang
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Disease ,medicine.disease ,Therapy naive ,Immune system ,Internal medicine ,medicine ,Profiling (information science) ,Non small cell ,Stage (cooking) ,Lung cancer ,business ,Multi platform - Abstract
Introduction: Differences in the host immune environment are thought to mediate heterogeneous treatment responses in non-small cell lung cancer (NSCLC). Unlike individual platform analyses, integrative analysis of multi-platform profiling allows for the discovery of novel interactions that expand our understanding of the disease. Utilizing the ImmunogenomiC prOfiling of NSCLC patient cohort (ICON), a prospective multi-omics protocol of operable early-stage NSCLC tumors with integrated immune, genomic, and clinical data, we hypothesized that multi-platform analyses would identify differences in the immune-genomic landscape that are associated with disease recurrence. Methods: Tumor and tumor-adjacent uninvolved lung was collected at resection; blood was collected before and after surgery. Tissue samples underwent WES, RNAseq, TCR sequencing (TCRseq), multiplex immunofluorescence (mIF), and RPPA profiling; tissue and blood (PBMC) samples were analyzed by flow cytometry. An integrated, inter-modality network was built using Spearman correlations between measurement pairs from different data modalities. Multivariate analysis was performed to adjust for stage and histology. Results: A total of 89 treatment-naïve patients with Stage 1-3 resected NSCLC (Squamous: 19; Non-squamous: 70) and 24 months of follow-up were analyzed (recurrence N = 24; no recurrence N = 65). The data network includes over 4,000 measurements linked by over 50,000 correlations. InfoMap, a community detection approach, was used to extract sub-network modules, which were used to contextualize the results of multivariate analysis. Tumors from patients with recurrence demonstrated decreased immune cell infiltration and activation including decreased cytotoxic CD8 T-cells (CD8+PD1+; fold-change (FC) = 0.898, p = 0.018; flow cytometry), decreased T-cell clonality (FC = 0.954, p = 0.017; TCRseq), and decreased tumor-associated macrophages (CD68+PD-L1+; FC = 0.426, p = 0.011; mIF). Furthermore, circulating CD8+ICOS+ activated T cells were decreased in patients with recurrence suggesting an impaired systemic anti-tumor immune response (FC = 0.552, p = 0.042; PBMC Flow). Finally, tumor-adjacent uninvolved lungs showed distinct T-cell phenotypes with accumulation of inactive CD8 T-cells (CD8+PD1-TIM3-) in patients with recurrence and increased populations of activated CD8 T-cells (CD8+PD1+) in patients without recurrence. Conclusion: Integrative multi-omic analysis suggests preserved anti-tumor immune surveillance in patients who are disease-free after 2 years from surgical resection with curative intent for treatment of NSCLC relative to patients with disease recurrence. Further analysis is ongoing to interrogate genomic and immune variables that are associated with disease recurrence. Citation Format: Neal Akhave, Stephanie Schmidt, Alexandre Reuben, Tina Cascone, Jianhua Zhang, Jun Li, Junya Fujimoto, Lauren A. Byers, Beatriz Sanchez-Espiridion, Lixia Diao, Jing Wang, Lorenzo Federico, Marie-Andree Forget, Daniel J. McGrail, Annikka Weissferdt, Shiaw-Yih Lin, Younghee Lee, Carmen Behrens, Ignacio I. Wistuba, Andrew Futreal, Ara Vaporciyan, Boris Sepesi, John V. Heymach, Chantale Bernatchez, Cara Haymaker, Jianjun Zhang, Christopher A. Bristow, Marcelo V. Negrao, Don L. Gibbons. Integrated multi-platform profiling of early-stage non-small cell lung cancer identifies relationship between disease recurrence and decreased native immune response in treatment-naïve resected NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 619.
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- 2021
24. Abstract 518: Immunogenomic correlates of response to combination immune checkpoint blockade in advanced sarcoma
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Celia Garcia-Prieto, Joshua Baguley, Shreyaskumar Patel, Akash Mitra, Neeta Somaiah, Beatriz E. Sanchez, Cara Haymaker, Grace Mathew, Alexander J. Lazar, Taylor Tate, Christina L. Roland, Emily Z. Keung, Anthony P. Conley, Heather Lin, Behrang Amini, Robert S. Benjamin, John A. Livingston, Wei-Lien Wang, Xingshi Song, Dejka M. Araujo, Luisa M. Solis, Chantale Bernatchez, Swati Gite, Maria Alejandra Zarzour, Ignacio I. Wistuba, Andrew Futreal, Najat C. Daw, Hannah C. Beird, Linghua Wang, Hussein Abdul-Hassan Tawbi, Vinod Ravi, Latasha Little, Jianhua Zhang, Curtis Gumbs, and Shaojun Zhang
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Cancer Research ,Oncology ,business.industry ,Cancer research ,Medicine ,Sarcoma ,business ,medicine.disease ,Immune checkpoint ,Blockade - Abstract
Sarcomas encompass a rare but highly diverse set of tumor malignancies, contributing disproportionately to years of life lost. Immune checkpoint blockade (ICB) has been successful across various tumor types; however, their efficacy and predictability in sarcomas remain unknown. We conducted a translational study using pre- and on-treatment tumor biopsies collected prospectively on a Phase II clinical trial (NCT02815995) evaluating the role of combination anti-PD-L1 and anti-CTLA-4 in 57 patients, enrolled across multiple histologies of metastatic sarcoma. We obtained tumor biopsies at baseline and after 6 weeks of treatment and performed whole-exome, T-cell repertoire (TCR) and RNA-sequencing, along with multiplexed-immunofluorescence (mIF).We deconvoluted substantial variability present in the tumor microenvironment (TME) within sarcomas and found instances of relatively inflamed tumors which failed to respond to ICB. However, amongst those potential molecular correlates of response analyzed, elevated levels of B-cells both at the transcriptome and through validation staining (p = 0.047 and p = 0.022) were most significantly correlated with response. In order to gain more insight into the phenotype and function of B-cells in contributing to response, we inferred BCR-templates and found higher levels of both IGH and IGL diversity (p = 0.0276 and p = 0. 0889 respectively) in responders to ICB. Additionally, we detected increased levels of hyperexpanded IGH clones at the on-treatment time point in patients that responded to therapy (p = 0.048). This B-cell enrichment was validated and found to be predictive of response (p = 0.043) in an independent sarcoma anti-PD-1 treated cohort with matched molecular data. Responsive tumors were also associated with higher levels of TCR richness indicating a strong association of diversity in the TCR of responders (p = 0.047). This work demonstrates the potential for multi-lineage immune cell enrichment and frames the potential molecular features of the TME that may influence response in ICB treated sarcomas. Citation Format: Akash Mitra, Neeta Somaiah, Anthony P. Conley, Behrang Amini, Heather Lin, Beatriz E. Sanchez, Celia Garcia-Prieto, Grace Mathew, Chantale Bernatchez, Vinod Ravi, Dejka Araujo, Maria A. Zarzour, John A. Livingston, Christina L. Roland, Najat Daw, Joshua Baguley, Wei-Lien Wang, Hannah Beird, Taylor Tate, Cara Haymaker, Latasha D. Little, Curtis Gumbs, Xingshi Song, Emily Z. Keung, Shaojun Zhang, Swati Gite, Jianhua Zhang, Luisa Solis, Hussein Tawbi, Linghua Wang, Shreyaskumar Patel, Robert S. Benjamin, Alexander J. Lazar, Ignacio I. Wistuba, Andrew Futreal. Immunogenomic correlates of response to combination immune checkpoint blockade in advanced sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 518.
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- 2021
25. Abstract 1670: Circulating biomarkers are associated with recurrence following complete resection of non-small cell lung cancer
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Alexandre Reuben, Younghee Lee, Mayra E. Vasquez, Don L. Gibbons, John V. Heymach, Boris Sepesi, Tina Cascone, Jianjun Zhang, Cara Haymaker, Ara A. Vaporciyan, Carlos A. Ramos, Chantale Bernatchez, Marcelo V. Negrao, Hai T. Tran, Annikka Weissferdt, Ignacio I. Wistuba, and Daniel J. McGrail
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Oncology ,Cancer Research ,medicine.medical_specialty ,Circulating biomarkers ,business.industry ,Internal medicine ,medicine ,Non small cell ,Lung cancer ,medicine.disease ,business ,Complete resection - Abstract
Background: We have previously demonstrated that the presence of a proinflammatory peripheral cytokine milieu correlates with high levels of circulating neutrophils at the time of surgery and reduced overall survival and recurrence-free survival. In this study, we hypothesized that functional immune features or states in circulation may indicate early tumor recurrence when assessed longitudinally. We also investigated whether potential deficiencies in peripheral immune functionality at the time of lung cancer resection could identify correlates with subsequent outcome. Methods: We performed flow cytometry and luminex profiling of blood samples collected from patients with stage I-IIIA resected NSCLC (n=150) and enrolled on the Immunogenomic profiling of NSCLC (ICON) prospective protocol. Patient characteristics include 75 adenocarcinomas, 30 squamous and 12 mixed or other histologies. Only patients who underwent primary cancer resection without neoadjuvant therapy were included. At a median follow up of 18.2 months, 37 patients had disease recurrence. Blood was collected at the time of primary lung cancer resection, at 4 weeks, and 4 months thereafter with PBMCs utilized for flow cytometry and plasma for cytokine assessment. Changes in cytokines were assessed by normalizing to baseline levels. Results: Larger tumors as well as advanced clinical and pathological stages were associated with higher frequencies of proliferating Ki67+CD4+ and Ki67+CD8+ T cells in circulation at time of resection, suggesting an activated circulating immune response. We identified novel strong correlations in the plasma between soluble BTLA and Tim3 (r= 0.87, p=1.74e-140), PD1 and CD80 (r=0.72, p=6.41e-74) and moderate correlations between soluble PD1 and PDL1 (r=0.39, p=8.41e-18). Efforts are ongoing to determine the association of specific circulating immune states with the presence of these soluble receptors. CD8+Tim3+ T cells (FC=5.2%, p=0.028) and CTLA4+NK cells (FC=47.7%, p=0.002) as well as CTLA4+Tregs (FC=25.2%, p=0.05) were found to be increased in circulation at pre-recurrence time points (either 4 weeks or 4 months) relative to resection. This suggests the emergence of a suppressive cell type as well as induction of specific checkpoint receptors on effector cells that correlate with tumor recurrence. Finally, we identified a cytokine signature associated with recurrence by testing three sets within the ICON cohort with a training set AUC = 0.76 and the test set AUC=0.72, which was validated in a third set of patients yielding an AUC = 0.76. Conclusions: We identified circulating immune features associated with initial tumor size and overall stage as well as unique associations among soluble proteins. Increased presence of potentially inhibited or suppressed CD8+ T cells and NK cells as well as Tregs are suggestive of mechanisms of immune suppression relative to tumor recurrence. Citation Format: Younghee Lee, Daniel McGrail, Hai Tran, Mayra E. Vasquez, Carlos Ramos, Alexandre Reuben, Ara A. Vaporciyan, Annikka Weissferdt, Chantale Bernatchez, Tina Cascone, Ignacio I. Wistuba, Jianjun Zhang, John Heymach, Marcelo V. Negrao, Don L. Gibbons, Boris Sepesi, Cara L. Haymaker. Circulating biomarkers are associated with recurrence following complete resection of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1670.
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- 2021
26. Metastatic Melanoma Patient Had a Complete Response with Clonal Expansion after Whole Brain Radiation and PD-1 Blockade
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Michael T. Tetzlaff, Wen-Jen Hwu, Ann Phillip, Irina Fernandez, Cara Haymaker, Adi Diab, Chantale Bernatchez, Paul D. Brown, Caitlin Creasy, Luis M Vence, Natalie McQuail, Courtney W. Hudgens, James P. Allison, Padmanee Sharma, Marc Uemura, Patrick Hwu, and Dae Won Kim
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0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Immunology ,Clone (cell biology) ,Pembrolizumab ,CD8-Positive T-Lymphocytes ,Antibodies, Monoclonal, Humanized ,Lymphocyte Activation ,Article ,Clonal Evolution ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,medicine ,Humans ,Lymphocyte Count ,Melanoma ,biology ,Brain Neoplasms ,business.industry ,Brain ,Cancer ,Immunotherapy ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Magnetic Resonance Imaging ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Monoclonal ,Cancer research ,biology.protein ,Female ,Cranial Irradiation ,Antibody ,business ,Biomarkers ,CD8 - Abstract
We report here on a patient with metastatic melanoma who had extensive brain metastases. After being treated with the sequential combination of whole brain radiation therapy followed by the PD-1–inhibitory antibody, pembrolizumab, the patient had a durable complete response. Retrospective laboratory studies of T cells revealed that, after treatment with anti-PD-1 commenced, effector CD8+ T cells in the blood expanded and the ratio of CD8+:Treg T cells increased. A CD8+ T-cell clone present in the initial brain metastases was expanded in the blood after anti-PD-1 treatment, which suggested an antitumor role for this clone. Immunohistochemical analysis confirmed the presence of CD8+ T cells and low PD-L1 expression in the brain metastases before immunotherapy initiation. This sequence of therapy may provide an option for melanoma patients with unresponsive brain metastases. Cancer Immunol Res; 5(2); 100–5. ©2017 AACR.
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- 2017
27. 1031P Tilsotolimod engages the TLR9 pathway to promote antigen presentation and type I IFN signaling in solid tumours
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Vivek Subbiah, Hans Minderman, Rolf Hultsch, Gregory Woodhead, Ravi Murthy, Shah Rahimian, Pete Anderson, Daniel Hendler, Igor Puzanov, Adi Diab, Charles Hennemeyer, Alain Algazi, Michal Lotem, Nadia Caplan, Jacob Schachter, Erkut Borazanci, C. Haymaker, Hani M. Babiker, S. Chunduru, and Chantale Bernatchez
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Oncology ,business.industry ,Antigen presentation ,Cancer research ,TLR9 ,Medicine ,Hematology ,business - Published
- 2020
28. Comprehensive T cell repertoire characterization of non-small cell lung cancer
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Roy S. Herbst, James P. Allison, Kelly Quek, Edwin R. Parra, Samantha Tippen, Harlan Robins, Chi Wan Chow, Alexandre Reuben, Runzhe Chen, Erik Yusko, Padmanee Sharma, Xizeng Mao, Jiexin Zhang, John V. Heymach, Patrick Hwu, Boris Sepesi, Jun Li, Yuanqing Ye, Jianhua Zhang, Humam Kadara, Carmen Behrens, Rebecca Thornton, Farrah Kheradmand, Neda Kalhor, Xin Hu, Latasha Little, P. Andrew Futreal, Paul Scheet, Alexandra Snyder, Tina Cascone, Sharon Benzeno, Don L. Gibbons, Won-Chul Lee, Xiaoke Liu, Veera Baladandayuthapani, Xifeng Wu, Jack Lee, Cesar A. Moran, Ignacio I. Wistuba, Ara A. Vaporciyan, Ali Jalali, Chunlin Wang, Junya Fujimoto, Xingzhi Song, Heather Lin, Curtis Gumbs, Mark M. Davis, Feng Wang, Ryan O. Emerson, Chantale Bernatchez, Jennifer A. Wargo, Shin Heng Chiou, Chang-Jiun Wu, Stephen G. Swisher, Marissa Vignali, Rachel M. Gittelman, Agda Karina Eterovic, and Jianjun Zhang
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0301 basic medicine ,Male ,Lung Neoplasms ,medicine.medical_treatment ,T-Lymphocytes ,General Physics and Astronomy ,Lymphocyte Activation ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cancer genomics ,T-cell receptor ,lcsh:Science ,Lung ,Multidisciplinary ,Middle Aged ,3. Good health ,ErbB Receptors ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Tumour immunology ,Female ,Adult ,T cell ,Science ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Immune system ,Antigen ,medicine ,Carcinoma ,Humans ,Lymphocyte Count ,Lung cancer ,Aged ,business.industry ,General Chemistry ,Immunotherapy ,medicine.disease ,Survival Analysis ,respiratory tract diseases ,Clone Cells ,030104 developmental biology ,Mutation ,Cancer research ,lcsh:Q ,business ,Non-small-cell lung cancer - Abstract
Immunotherapy targeting T cells is increasingly utilized to treat solid tumors including non-small cell lung cancer (NSCLC). This requires a better understanding of the T cells in the lungs of patients with NSCLC. Here, we report T cell repertoire analysis in a cohort of 236 early-stage NSCLC patients. T cell repertoire attributes are associated with clinicopathologic features, mutational and immune landscape. A considerable proportion of the most prevalent T cells in tumors are also prevalent in the uninvolved tumor-adjacent lungs and appear specific to shared background mutations or viral infections. Patients with higher T cell repertoire homology between the tumor and uninvolved tumor-adjacent lung, suggesting a less tumor-focused T cell response, exhibit inferior survival. These findings indicate that a concise understanding of antigens and T cells in NSCLC is needed to improve therapeutic efficacy and reduce toxicity with immunotherapy, particularly adoptive T cell therapy., Relevant features of T cell repertoire in human cancer remain to be delineated. Here the authors show, by TCR sequencing in a large cohort of lung cancer patients, that while a majority of T cell clones are shared between tumor and adjacent lung tissue, less frequent tumor-unique T cell clones correlate with worse prognosis.
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- 2019
29. Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16-Related Cancer A Phase 2 Clinical Trial
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J. Jack Lee, William N. William, Erminia Massarelli, Faye M. Johnson, Young Uk Kim, Michael A. Curran, Cornelis J. M. Melief, Bonnie S. Glisson, Jing Wang, Ignacio I. Wistuba, Merrill S. Kies, Hai T. Tran, Chantale Bernatchez, Cara Haymaker, Renata Ferrarotto, Tomas Zecchini Barrese, Ming Guo, Lerong Li, Jaime Rodriguez Canales, Lei Feng, and Sjoerd H. van der Burg
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Programmed Cell Death 1 Receptor ,Phases of clinical research ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Randomized controlled trial ,law ,Internal medicine ,Neoplasms ,medicine ,Humans ,030212 general & internal medicine ,Progression-free survival ,Papillomavirus Vaccines ,Aged ,Original Investigation ,Human papillomavirus 16 ,business.industry ,Papillomavirus Infections ,Cancer ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Vaccination ,Clinical trial ,Nivolumab ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,business - Abstract
Importance In recurrent human papilloma virus (HPV)–driven cancer, immune checkpoint blockade with anti–programmed cell death 1 (PD-1) antibodies produces tumor regression in only a minority of patients. Therapeutic HPV vaccines have produced strong immune responses to HPV-16, but vaccination alone has been ineffective for invasive cancer. Objective To determine whether the efficacy of nivolumab, an anti–PD-1 immune checkpoint antibody, is amplified through treatment with ISA 101, a synthetic long-peptide HPV-16 vaccine inducing HPV-specific T cells, in patients with incurable HPV-16–positive cancer. Design, Setting, and Participants In this single-arm, single-center phase 2 clinical trial, 24 patients with incurable HPV-16–positive cancer were enrolled from December 23, 2015, to December 12, 2016. Duration of follow-up for censored patients was 12.2 months through August 31, 2017. Interventions The vaccine ISA101, 100 μg/peptide, was given subcutaneously on days 1, 22, and 50. Nivolumab, 3 mg/kg, was given intravenously every 2 weeks beginning day 8 for up to 1 year. Main Outcomes and Measures Assessment of efficacy reflected in the overall response rate (per Response Evaluation Criteria in Solid Tumors, version 1.1). Results Of the 24 patients (4 women and 20 men; 22 with oropharyngeal cancer; median age, 60 years [range, 36-73 years]), the overall response rate was 33% (8 patients; 90% CI, 19%-50%). Median duration of response was 10.3 months (95% CI, 10.3 months to inestimable). Five of 8 patients remain in response. Median progression-free survival was 2.7 months (95% CI, 2.5-9.4 months). Median overall survival was 17.5 months (95% CI, 17.5 months to inestimable). Grades 3 to 4 toxicity occurred in 2 patients (asymptomatic grade 3 transaminase level elevation in 1 patient and grade 4 lipase elevation in 1 patient), requiring discontinuation of nivolumab therapy. Conclusions and Relevance The overall response rate of 33% and median overall survival of 17.5 months is promising compared with PD-1 inhibition alone in similar patients. A randomized clinical trial to confirm the contribution of HPV-16 vaccination to tumoricidal effects of PD-1 inhibition is warranted for further study. Trial Registration ClinicalTrials.gov identifier:NCT02426892
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- 2019
30. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer
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Maria Gisela Higa, Jorge Blando, Matthew H.G. Katz, Luis M Vence, Huamin Wang, Alejandro M. Sepulveda, Padmanee Sharma, Anu Sharma, Chantale Bernatchez, Jennifer A. Wargo, Cassian Yee, Sreyashi Basu, Michael J. Overman, Michael T. Tetzlaff, Michael Sharp, Shalini S. Yadav, Russell Broaddus, Gauri R. Varadhachary, Christine A. Iacobuzio-Donahue, Anirban Maitra, James P. Allison, Jiseong Kim, and Hao Zhao
- Subjects
0301 basic medicine ,B7 Antigens ,medicine.medical_treatment ,T cell ,Adenocarcinoma ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Pancreatic tumor ,Pancreatic cancer ,parasitic diseases ,medicine ,Tumor Microenvironment ,Humans ,Melanoma ,Tumor microenvironment ,Multidisciplinary ,business.industry ,Immunotherapy ,Biological Sciences ,medicine.disease ,Immune checkpoint ,Pancreatic Neoplasms ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,business ,Carcinoma, Pancreatic Ductal - Abstract
Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67). We found that a pancreatic tumor has minimal to moderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68(+) macrophages and VISTA(+) cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer.
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- 2019
31. Efficacy of Pembrolizumab in Patients with Advanced Rare Cancers
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Jing Gong, Matthew Campbell, Joud Hajjar, Vivek Subbiah, Linghua Wang, David S. Hong, Lacey M. McQuinn, Chantale Bernatchez, S. Pant, Gauri R. Varadhachary, TImothy A. Yap, Bettzy Stephen, Sharjeel H. Sabir, Apostolia M. Tsimberidou, Kanwal P. S. Raghav, M. Frumovitz, Jeane M. Painter, Nizar M. Tannir, Kenneth R. Hess, Daniel D. Karp, Jordi Rodon Ahnert, Rivka R. Colen, Shi-Ming Tu, Vinod Ravi, Renata Ferrarotto, Aung Naing, Anas Ashalwa, Siqing Fu, Ecaterina E. Ileana Dumbrava, Saria Khan, Coya Tapia, Camilo Jimenez, Filip Janku, Sarina Anne Piha-Paul, Mingxuan Xu, Mouhammed Amir Habra, Richard Simon, Sara Ahmed, and Funda Meric-Bernstam
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,In patient ,Pembrolizumab ,business - Published
- 2019
32. A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
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Salah Eddine Bentebibel, Jonathan Zalevsky, Michael T. Tetzlaff, Ute Hoch, Michael E. Hurwitz, Nizar M. Tannir, Patrick Hwu, Sandra Aung, Chantale Bernatchez, Mario Sznol, Harriet M. Kluger, Christie Fanton, Courtney W. Hudgens, Mary Tagliaferri, Brendan D. Curti, Cara Haymaker, and Adi Diab
- Subjects
0301 basic medicine ,Agonist ,medicine.drug_class ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Antineoplastic Agents ,CD8-Positive T-Lymphocytes ,Polyethylene Glycols ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,Neoplasms ,Tumor Microenvironment ,Medicine ,Humans ,IL-2 receptor ,Tumor microenvironment ,business.industry ,Interleukin-2 Receptor alpha Subunit ,Immunotherapy ,030104 developmental biology ,Cytokine ,Treatment Outcome ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Cancer research ,Interleukin-2 ,business ,CD8 ,Biomarkers ,Signal Transduction - Abstract
NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. Significance: We believe that IL2- and IL2 pathway–targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors. See related commentary by Sullivan, p. 694. This article is highlighted in the In This Issue feature, p. 681
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- 2018
33. 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018)
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Sekwon Jang, Scott S. Tykodi, Igor Puzanov, Fiore Cattaruzza, Ute Hoch, Alexander Spira, Ewa Kalinka Warzocha, Karl D. Lewis, Jonathan Zalevsky, Gregory A. Daniels, Mike Hurwitz, Brendan D. Curti, Dariusz Sawka, Alison L. Hannah, Mary Tagliaferri, Chantale Bernatchez, Wendy L. Clemens, Christie Fanton, Mario Sznol, Cara Haymaker, James Larkin, Adi Diab, Michael H. Wong, Michele Maio, Sandra Aung, Mehmet Asim Bilen, Giovanni Grignani, Daniel Cho, Salah Eddine Bentebibel, Ahsan Naqi Rizwan, Michael Imperiale, Ernesto Iaccucci, and Paul Lorigan
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Pharmacology ,Oncology ,0303 health sciences ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immunology ,Immune monitoring ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Stage iv melanoma ,Molecular Medicine ,Immunology and Allergy ,Nivolumab ,business ,030304 developmental biology - Published
- 2018
34. Abstract PR15: CD74 regulated inflammatory pattern is associated with TIL growth and favorable response to adoptive immunotherapy
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Elizabeth A. Grimm, Caitlin Creasy, Jason Roszik, Patrick Hwu, Dai-Ogata, Sun-Hee Kim, Suhendan Ekmekcioglu, and Chantale Bernatchez
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Cancer Research ,Tumor microenvironment ,CD74 ,biology ,business.industry ,medicine.medical_treatment ,Melanoma ,Antigen presentation ,CD44 ,Immunotherapy ,medicine.disease ,Immune system ,Oncology ,medicine ,biology.protein ,Cancer research ,Macrophage migration inhibitory factor ,business - Abstract
We previously reported that in Stage III melanoma patients’ tumors, positive expression of CD74 together with low or absent Macrophage Migration Inhibitory Factor (MIF) associates with favorable prognosis (Ekmekcioglu et al., CCR 2016). As both are known to be regulated by IFN-g, we suggest a differential IFN-g response as well as a novel role for CD74 that may be exploited to improve patient outcome. Our further analyses of The Cancer Genome Atlas (TCGA) datasets confirmed the role of CD74 in prognosis for patient survival, which is likely attributed to regulation of MHC-Class II and antigen presentation in the tumor microenvironment. Immune infiltration of T cells (TIL) into the melanoma microenvironment has been associated with improved survival for some patients, and also has been exploited to grow TIL in vitro for adoptive therapy. However, prognostic significance of immune infiltrating cells in melanoma and other tumors remains a relatively new concept, and markers related to suppressive versus active functional TIL remain unclear. From an ongoing clinical trial using TIL intended for adoptive immunotherapy, we have studied the melanoma patient tumor specimens (FFPE) from 20 patients whose autologous TIL lines grew to sufficient number for possible use clinically. We also examined another 20 sets of melanoma tumor from which the TIL did not grow or did not grow well. We analyzed the differences in the two groups of tumors (40 total FFPE) for CD74 regulated pathway features and inflammatory marker expression. CD74 regulated markers included CD44, MIF, and downstream inflammatory targets including inducible nitric oxide synthase (iNOS), nitrotyrosine (NT) and microsomal prostaglandin E synthase-1 (mPGES1). Our findings confirm our previous report in that tumor CD74 expression significantly associates with favorable OS and PFS (both, p=0.0038) and provides new data that in this set of patients the CD74 also correlates with best irRC of TIL treated patients. New findings include that the NT expression in tumor cells associated with poor TIL growth (p=0.014), as well as lack of clinical response to TIL treatment (p=0.02). We have also found that tumor cell-derived MIF and iNOS expression correlate with unfavorable prognosis for both OS and PFS (p=0.016 and 0.018, respectively). The iNOS and MIF coexpression characteristics and cellular distributions in the tumor are currently under way. In conclusion, we have identified the protein expression of CD74, MIF and of iNOS as providing survival information, and proposed that CD74+/MIF-/iNOS- together be considered to form a “signature” of good prognosis in general melanoma outcomes as well as TIL growth and favorable responses for these patients. Use of this signature for selecting patients for entry into TIL and possibly other immunotherapy trials, as well as research on the differential pathways of IFN-g signaling in melanoma, appear as important areas for future mechanistic research to improve patient outcome. This abstract is also being presented as Poster B14. Citation Format: Dai-Ogata, Caitlin A. Creasy, Sun-Hee Kim, Jason Roszik, Patrick Hwu, Elizabeth A. Grimm, Chantale Bernatchez, Suhendan Ekmekcioglu. CD74 regulated inflammatory pattern is associated with TIL growth and favorable response to adoptive immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR15.
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- 2020
35. Abstract CT134: Tilsotolimod engages the TLR9 pathway to promote antigen presentation and Type-I IFN signaling in solid tumors
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Shah Rahimian, Asim Ali, Erkut Borazanci, Peter M. Anderson, Vivek Subbiah, Rolf Hultsch, Sri Chunduru, Alain Algazi, Corinne Maurice-Dror, Igor Puzanov, Hani M. Babiker, Nadia Caplan, Chantale Bernatchez, Ravi Murthy, Gregory Woodhead, Daniel Hendler, Jacob Schachter, Michal Lotem, Cara Haymaker, Adi Diab, Charles Hennemeyer, and Hans Minderman
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Oncology ,Cancer Research ,medicine.medical_specialty ,Tumor microenvironment ,LAG3 ,business.industry ,Melanoma ,Cancer ,medicine.disease ,Immune checkpoint ,Immune system ,Internal medicine ,Cohort ,Medicine ,Chills ,medicine.symptom ,business - Abstract
Background: Tilsotolimod, an investigational Toll-like receptor 9 (TLR9) agonist, modulates the tumor immune microenvironment and has single-agent antitumor activity in preclinical models. The ILLUMINATE-101 phase 1b study (NCT03052205) explored the safety, efficacy, and immune effects of intratumoral tilsotolimod in multiple solid tumors. Methods: Adults with a histologically- or cytologically-confirmed diagnosis of cancer not amenable to curative therapies received intratumoral tilsotolimod 8, 16, 23, or 32 mg into a single lesion on Days 1, 8, and 15 of Cycle 1 and Day 1 of each subsequent 3-week cycle, for up to 17 cycles. Additionally, patients with advanced melanoma were enrolled into an expansion cohort at the recommended phase 2 dose of 8 mg. The primary objective was to characterize safety (dose escalation cohort) and efficacy (expansion cohort). Secondary objectives included pharmacokinetics of tilsotolimod. Immunological assessment of injected and non-injected tumors was an exploratory objective. Blood samples and tumor biopsies of injected lesions were obtained at baseline and 24 hours post treatment for immune analyses. Results: A total of 54 patients were enrolled. Of the 38 patients in the dose escalation cohort, 35 had metastatic disease. Patients in this cohort had a median of 7 prior lines of treatment, and the most common cancer types were pancreatic (12 patients) and colorectal (7 patients). All 16 patients in the melanoma cohort had metastatic disease with a median of 3 lines of prior therapy, and 10 patients had elevated LDH. Injected lesions were deep and required interventional radiology in 52 of 54 patients. No dose-limiting toxicities were observed. The most common treatment-related adverse events were pyrexia, fatigue, chills, nausea, and vomiting. Compared to pretreatment, biopsies of injected tumors at 24 hours showed increased activation of the Type-I IFN pathway, upregulation of MHC class I/II, IFNγ expression, and expression of multiple immune checkpoints (i.e. PD-1, LAG3). Of the 35 evaluable patients in the dose escalation cohort, 12 (34%) achieved a best overall response of stable disease (SD). Of the 16 evaluable patients in the melanoma cohort, 3 had SD, 1 who had a 35% tumor reduction with no confirmatory scan. Conclusions: Tilsotolimod was generally well tolerated and induced alterations in the tumor microenvironment, including immune checkpoint upregulation, activation of dendritic cells, and induction of Type-I IFN signaling. Additional clinical studies of tilsotolimod in combination with checkpoint inhibitors are underway (NCT03445533, NCT03865082, and NCT02644967). Citation Format: Hani M. Babiker, Vivek Subbiah, Asim Ali, Alain Algazi, Jacob Schachter, Michal Lotem, Corinne Maurice-Dror, Daniel Hendler, Shah Rahimian, Hans Minderman, Cara Haymaker, Chantale Bernatchez, Ravi Murthy, Rolf Hultsch, Nadia Caplan, Gregory Woodhead, Charles Hennemeyer, Sri Chunduru, Peter Anderson, Adi Diab, Erkut Borazanci, Igor Puzanov. Tilsotolimod engages the TLR9 pathway to promote antigen presentation and Type-I IFN signaling in solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT134.
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- 2020
36. CIMAC-CIDC CyTOF harmonization
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Salah Eddine Bentebibel, Nicholas F. Fernandez, Sean C. Bendall, Beatriz Sanchez Espiridion, Emily M. Thrash, Karen A. Millerchip, Natalia Sigal, Bita Sahaf, Adeeb Rahman, Chantale Bernatchez, Sacha Gnjatic, Ignacio I. Wistuba, Mina Pichavant, Emily M. McWilliams, Cara Haymaker, Diane Marie Del Valle, Caroline Duault, Holden T. Maecker, and Melanie Davila
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Harmonization ,Immune monitoring ,medicine.disease ,Internal medicine ,medicine ,business ,Commons ,Cancer immunology - Abstract
e15242 Background: The Cancer Immune Monitoring and Analysis Centers – Cancer Immunology Data Commons (CIMAC-CIDC) network is a National Cancer Institute-funded initiative to identify biomarkers of mechanisms and response to cancer immunotherapy clinical trials, using state-of-the-art assay technologies. A primary platform for CIMAC-CIDC biomarker studies is CyTOF mass cytometry, which is performed at all four CIMAC laboratories. Methods: To test the ability to generate comparable data across labs, a cross-site harmonization effort was undertaken. We first harmonized SOPs between centers. Because of a new acquisition protocol introduced by the vendor (Fluidigm), we also tested this protocol across sites before finalizing the harmonized SOP. We then performed a cross-site assay harmonization experiment, using 5 shared cryopreserved PBMC samples and one lyophilized control cell preparation, along with a shared lyophilized antibody cocktail consisting of 14 markers, as validated in the HIPC consortium, plus CD45. These reagents and samples were distributed to the four sites, and FCS files were centrally analyzed by both manual gating and automated methods (Astrolabe). Results: Average CVs across sites for each cell population were reported and compared to a previous multisite CyTOF study. Once a cell recovery issue at two sites was resolved, this experiment resulted in inter-site reproducibility of under 20% CV for most cell subsets, very similar to the previous study. Conclusions: These results emphasize the ability to reproduce CyTOF across sites, and also highlights procedures, such as use of spike-in control samples, useful for tracking variability in this assay.
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- 2020
37. Successful tumor-infiltrating lymphocyte (TIL) growth from uveal melanoma (UM) using a three-signal (3.0) method
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Meredith S. Pelster, Stephen K. Gruschkus, Marie-Andree Forget, Cara Haymaker, Rodabe N. Amaria, Chantale Bernatchez, Sapna Pradyuman Patel, Patrick Hwu, and Dan S. Gombos
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Cancer Research ,Adoptive cell transfer ,Oncology ,Tumor-infiltrating lymphocytes ,business.industry ,Melanoma ,medicine ,Cancer research ,hemic and immune systems ,chemical and pharmacologic phenomena ,medicine.disease ,business ,Rare cancer - Abstract
3027 Background: Metastatic UM is a rare cancer with poor response rates to systemic therapy. Adoptive transfer of patient-specific TIL may represent the best strategy for treatment. TIL are harvested from primary or metastatic tumors and initially expanded in culture with high dose IL-2 prior to undergoing rapid expansion protocol and therapeutic administration. Here, we report improved rates of initial expansion using a previously described TIL 3.0 method which utilizes dual agonistic antibodies to TCR and 4-1BB (Urelumab) for stimulation, respectively, with high dose IL-2, compared to the traditional method. Methods: Between 2006 and 2019, patients were consented for TIL harvest from either primary or metastatic UM tumors. Demographics, clinical features, and outcomes of the TIL initial expansion were collected. Success rates, number of cells expanded, and days in culture for the two methods were analyzed using partially overlapping samples t-tests and z-tests. Results: There were 85 harvests and expansions from 76 patients using the traditional method and 32 expansions from 30 patients using TIL 3.0. Initial TIL expansion was successful in 97% of TIL 3.0 harvests compared to 35% for the traditional method (p < 0.001). More TIL were expanded with TIL 3.0 compared to the traditional method (291.3 million cells vs. 88.6 million cells, p < 0.001), and fewer days were required in culture (18.5 vs. 29.0, p < 0.001). Both primary UM harvests and metastatic harvests were more successful with TIL 3.0 (90% vs. 12% for primary, p < 0.001, and 100% vs. 42% for metastatic, p < 0.001). Conclusions: Expansion of UM tumors via the TIL 3.0 method led to successful growth in 97% of harvests. Therapeutic administration to patients with TIL 3.0 is under active investigation. [Table: see text]
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- 2020
38. Phase 2 study of pembrolizumab in patients with advanced rare cancers
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Sarjeel H. Sabir, Chantale Bernatchez, Richard Simon, Bettzy Stephen, Ecaterina Ileana Dumbrava, Vivek Subbiah, Lacey McQuinn, Filip Janku, Jeane Painter, Nizar M. Tannir, Funda Meric-Bernstam, Jordi Rodon Ahnert, Anas Alshawa, Linghua Wang, Shubham Pant, Kanwal Pratap Singh Raghav, Apostolia Maria Tsimberidou, Shi Ming Tu, Michael Frumovitz, Abulrahman Abonofal, Camilo Jimenez, Siqing Fu, Timothy A. Yap, Aung Naing, Sarina Anne Piha-Paul, Daniel D. Karp, Matthew Campbell, Saria Khan, Gauri R. Varadhachary, Kenneth R. Hess, Vinod Ravi, Coya Tapia, Mingxuan Xu, Renata Ferrarotto, Sara Ahmed, David S. Hong, Jing Gong, Joud Hajjar, Mouhammed Amir Habra, and Rivka R. Colen
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Immunology ,Phases of clinical research ,tumours ,Pembrolizumab ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Carcinoma ,medicine ,Clinical endpoint ,Immunology and Allergy ,Adverse effect ,Clinical/Translational Cancer Immunotherapy ,Pharmacology ,business.industry ,medicine.disease ,Rash ,3. Good health ,030104 developmental biology ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Cohort ,Molecular Medicine ,medicine.symptom ,business ,sub_biomedicalsciences - Abstract
BackgroundPatients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers.MethodsIn this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR).ResultsA total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma–pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug.ConclusionsThe favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma–pheochromocytoma supports further evaluation of pembrolizumab in this patient population.Trial registration numberNCT02721732
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- 2020
39. Resident Breast T-cells: The Troops Are Already There
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Nicholas Navin, Chantale Bernatchez, and Aislyn Schalck
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Disease progression ,MEDLINE ,RNA ,medicine.disease ,Article ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Text mining ,Breast cancer ,Nat ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Molecular Medicine ,business ,Molecular Biology ,Value (mathematics) ,Immunologic memory - Abstract
The role of tissue-resident memory T (TRM) cells in breast cancer progression has been difficult to study. Savas et al. [1] (Nat. Med. 2018;24:986-993) used single-cell RNA sequencing to identify TRM cells in triple-negative breast cancer patients and demonstrated their prognostic value for predicting survival.
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- 2018
40. P2.04-19 Neoadjuvant Chemotherapy Is Associated with Immunogenic Cell Death and Increased T Cell Infiltration in Early-Stage NSCLC
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J. Heymach, Tatiana Karpinets, Qi Wang, A. Vaporciyan, Alexandre Reuben, Carmen Behrens, Lorenzo Federico, I. I. Wistuba, J. Li, Kyle G. Mitchell, J. Wang, Emily Roarty, Marcelo V. Negrao, Boris Sepesi, Pierre Olivier Gaudreau, Daniel R. Gomez, Lixia Diao, Erin M. Corsini, J. Zhang, Don L. Gibbons, Tina Cascone, Hai T. Tran, Annikka Weissferdt, Edwin R. Parra, Chantale Bernatchez, A.M. Correa, and Cara Haymaker
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Pulmonary and Respiratory Medicine ,Chemotherapy ,Oncology ,business.industry ,medicine.medical_treatment ,T cell infiltration ,Cancer research ,Medicine ,Immunogenic cell death ,Stage (cooking) ,business - Published
- 2019
41. Safety, efficacy, and immune effects of intratumoral tilsotolimod in patients with refractory solid tumours: Updated results from ILLUMINATE-101
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Hans Minderman, Shah Rahimian, S. Chunduru, Vivek Subbiah, Cara Haymaker, Adi Diab, Hani M. Babiker, Erkut Borazanci, G. Bindra, Orla Maguire, Peter M. Anderson, Chantale Bernatchez, I. Iverson, and Igor Puzanov
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Melanoma ,Phases of clinical research ,Ipilimumab ,Hematology ,medicine.disease ,Immune checkpoint ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Nivolumab ,business ,Adverse effect ,medicine.drug - Abstract
Background Tilsotolimod, a synthetic toll-like receptor 9 (TLR9) agonist, modulates the tumor immune microenvironment and has antitumor activity as monotherapy in preclinical models. In the ILLUMINATE-204 phase I/II study of tilsotolimod in combination with ipilimumab in patients with refractory melanoma, increased antitumor immune activity was observed in injected and uninjected tumors at 24 hours following tilsotolimod treatment. The ILLUMINATE-101 phase Ib study explored the safety, efficacy, and immune effects of tilsotolimod monotherapy in multiple solid tumors. Methods Adults with histologically or cytologically confirmed diagnosis of cancer not amenable to curative therapies received intratumoral tilsotolimod in doses escalating from 8 mg to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced melanoma were enrolled into an expansion cohort at the 8-mg dose, the recommended phase II dose established for melanoma. Objectives included characterizing safety and efficacy, and immunological assessment. Blood samples and tumor biopsies of injected and distal lesions were obtained at baseline and 24 hours post treatment for immune analyses. Results As of May 6 2019, 54 patients have been enrolled, including 38 patients into the dose evaluation portion and 16 patients into the melanoma expansion cohort. No dose-limiting toxicities were observed. The most common treatment-related adverse events were fever, fatigue, and chills. Within 24 hours, fresh tumor biopsies showed increased gene expression for multiple immune checkpoint pathways, increased IFN gamma levels, activation of the type 1 IFN pathway, and upregulation of MHC class I and II, compared to pretreatment biopsies. Of 43 evaluable patients, 15 (35%) had a RECIST v1.1 disease assessment of stable disease (duration 1.2 to 11.1 months, 1 patient ongoing). Conclusions Tilsotolimod was well tolerated and induced robust alterations in the tumor microenvironment, including immune checkpoint upregulation, activation of dendritic cells, and induction of Type 1 IFN signaling. A phase II study of tilsotolimod in combination with nivolumab and ipilimumab has been initiated for the treatment of multiple solid tumors (ILLUMINATE-206; NCT03865082). Clinical trial identification NCT03052205. Editorial acknowledgement Ted Everson, Idera Pharmaceuticals, Inc. Legal entity responsible for the study Idera Pharmaceuticals, Inc. Funding Idera Pharmaceuticals, Inc. Disclosure H. Babiker: Advisory / Consultancy: Endocyte; Advisory / Consultancy: Celgene. V. Subbiah: Advisory / Consultancy: Idera Pharmaceuticals; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: Loxo Oncology. S. Rahimian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. C. Haymaker: Research grant / Funding (institution): Idera Pharmaceuticals. C. Bernatchez: Research grant / Funding (institution): Idera Pharmaceuticals. G. Bindra: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. I. Iverson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. S. Chunduru: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. A. Diab: Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: Nektar Therapeutics; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy: Jounce Therapeutics; Honoraria (self): Novartis; Advisory / Consultancy: Idera. All other authors have declared no conflicts of interest.
- Published
- 2019
42. Prospective analysis of adoptive TIL therapy in patients with metastatic melanoma: response, impact of anti-CTLA4, and biomarkers to predict clinical outcome
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Carlos A. Torres-Cabala, Jeffrey E. Gershenwald, Jason Roszik, Vruti Patel, Wen-Jen Hwu, Anthony Lucci, M. I. Ross, Arely Wahl, Orenthial J. Fulbright, Yuzhong Jeff Meng, Christopher Toth, Tatiana Karpinets, Cara Haymaker, Chantell M. Farinas, Sapna Pradyuman Patel, Adi Diab, Caitlin Creasy, Patrick Hwu, Renjith Ramachandran, Jeffrey E. Lee, Isabella C. Glitza, Ankit Bhatta, Destiny Joy Carpio, Rodabe N. Amaria, Esteban Flores, Suzanne Cain, Michael K. Wong, Laszlo Radvanyi, Rameen Beroukhim, Portia G. Velasquez, Hussein Abdul-Hassan Tawbi, Chantale Bernatchez, Carol Vaughn, Shawne T. Thorsen, Marie Andrée Forget, Michael A. Davies, Young Uk Kim, Seth Wardell, Janice N. Cormier, Scott E. Woodman, Jennifer A. Wargo, Rahmatu Mansaray, Richard E. Royal, Rene J. Tavera, Audrey M. Gonzalez, Kenneth R. Hess, and Donastas Sakellariou-Thompson
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,BTLA ,chemical and pharmacologic phenomena ,Immunotherapy, Adoptive ,Article ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,Internal medicine ,medicine ,Combined Modality Therapy ,Humans ,CTLA-4 Antigen ,Progression-free survival ,Neoplasm Metastasis ,Melanoma ,Aged ,business.industry ,Interleukin-9 ,Cancer ,hemic and immune systems ,Neoplasms, Second Primary ,Immunotherapy ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Blockade ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Female ,business - Abstract
Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome. Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416–28. ©2018 AACR.
- Published
- 2018
43. Targeting the HGF/MET Axis Counters Primary Resistance to KIT Inhibition in KIT-Mutant Melanoma
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Wei-Lien Wang, Charuta Kale, Cara Haymaker, Meredith Ann McKean, David S. Hong, Lauren E. Haydu, Mark J. Routbort, Alexander J. Lazar, Elizabeth A. Grimm, Chantale Bernatchez, Agda Karina Eterovic, Fernando Carapeto, Xiaoxing Yu, Scott E. Woodman, Sun-Hee Kim, Mariana Petaccia de Macedo, Junna Oba, Shiraj Sen, and John S. Van Arnam
- Subjects
0301 basic medicine ,Cancer Research ,Primary (chemistry) ,business.industry ,Melanoma ,Mutant ,medicine.disease ,Article ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Text mining ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,business - Published
- 2018
44. TIL therapy and anti-CTLA4: can they co-exist?
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Rodabe N. Amaria, Cara Haymaker, Chantale Bernatchez, and Marie Andrée Forget
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CTLA4 ,Editorial ,Oncology ,Metastatic melanoma ,business.industry ,MEDLINE ,Cancer research ,Medicine ,Anti ctla4 ,TIL ,business ,metastatic melanoma - Published
- 2019
45. Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2
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Wen-Jen Hwu, Ian E. McCutcheon, Michelle Rohlfs, Roland L. Bassett, Isabella C. Glitza, Chantale Bernatchez, Rodabe N. Amaria, Patrick Hwu, Amy B. Heimberger, Michael A. Davies, Hussein Abdul-Hassan Tawbi, Nicholas Papadopoulos, Sapna Pradyuman Patel, Adi Diab, Scott E. Woodman, Cassian Yee, Michael K. Wong, and Nandita Guha-Thakurta
- Subjects
Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,03 medical and health sciences ,intrathecal therapy ,0302 clinical medicine ,Internal medicine ,Cytology ,medicine ,Ommaya reservoir ,melanoma ,Craniotomy ,Intracranial pressure ,Original Research ,Univariate analysis ,leptomeningeal disease ,business.industry ,Retrospective cohort study ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Concomitant ,Cohort ,interleukin-2 ,business ,030217 neurology & neurosurgery - Abstract
Objectives Metastatic melanoma patients with leptomeningeal disease (LMD) have an extremely poor prognosis, with a median survival measured in weeks, and few treatment options. Outcomes of a retrospective cohort of patients with LMD that were treated with intrathecal interleukin-2 (IT IL-2) were reviewed to assess the long-term efficacy of this therapy. Methods The records of metastatic melanoma patients with LMD who were treated with IT IL-2 from 2006 to 2014 in a Compassionate Investigational New Drug study were reviewed. IL-2 (1.2 mIU) was administered intrathecally via Ommaya reservoir up to five times per week in the inpatient setting for 4 weeks; patients with good tolerance and clinical benefit received maintenance IT IL-2 every 1–3 months thereafter. Results The cohort included 43 patients. The median age of the patients was 47 years (range 18–71), and 32 (74%) were male. 23 patients (53%) had positive cerebrospinal fluid (CSF) cytology and radiographic evidence of LMD, 8 (19%) had positive CSF cytology only, 9 (21%) had radiographic evidence only and 3 (7%) were diagnosed based on pathology review after craniotomy. The median overall survival (OS) from initiation of IT IL-2 was 7.8 months (range, 0.4–90.8 months), with 1-year, 2-year and 5-year OS rates of 36%, 26% and 13%. The presence of neurological symptoms (HR 2.1, P=0.03), positive baseline CSF cytology (HR 4.1, P=0.001) and concomitant use of targeted therapy (HR 3.0, P=0.02) was associated with shorter OS on univariate analysis. All patients developed symptoms due to increased intracranial pressure which was managed with supportive medications and/or CSF removal, and there were no treatment-related deaths. Conclusion These results demonstrate that despite their historically dismal prognosis a subset of metastatic melanoma patients with LMD treated with IT IL-2 can achieve long-term survival, but these data need to be verified in a prospective trial setting.
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- 2017
46. A Novel Method to Generate and Expand Clinical-Grade, Genetically Modified, Tumor-Infiltrating Lymphocytes
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Chantale Bernatchez, Shawne T. Thorsen, Audrey M. Gonzalez, Weiyi Peng, Shruti Malu, Seth Wardell, Arely Wahl, Rodabe N. Amaria, Esteban Flores, Cara Haymaker, Rene J. Tavera, Patrick Hwu, Renjith Ramachandran, Orenthial J. Fulbright, Chistopher Leroy Toth, Marie Andrée Forget, and Minying Zhang
- Subjects
lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Immunology ,chemical and pharmacologic phenomena ,Viral vector ,Cell therapy ,Good Manufacturing Practice ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,clinical-grade ,Methods ,genetic modification ,Immunology and Allergy ,Medicine ,business.industry ,Tumor-infiltrating lymphocytes ,retroviral-transduction ,Cancer ,adoptive cell therapy ,hemic and immune systems ,Clinical grade ,medicine.disease ,First generation ,3. Good health ,Genetically modified organism ,030104 developmental biology ,tumor-infiltrating lymphocytes ,030220 oncology & carcinogenesis ,Cancer research ,lcsh:RC581-607 ,business - Abstract
Following the clinical success achieved with the first generation of adoptive cell therapy (ACT) utilizing in vitro expanded tumor-infiltrating lymphocytes (TILs), the second and third generations of TIL ACT are evolving toward the use of genetically modified TIL. TIL therapy generally involves the transfer of a high number of TIL, ranging from 109 to 1011 cells. One of the technical difficulties in genetically modifying TIL, using a retroviral vector, is the ability to achieve large expansion of transduced TIL, while keeping the technique suitable to a Good Manufacturing Practices (GMP) environment. Consequently, we developed and optimized a novel method for the efficient production of large numbers of GMP-grade, gene-modified TIL for the treatment of patients with ACT. The chemokine receptor CXCR2 was used as the gene of interest for methodology development. The optimized procedure is currently used in the production of gene-modified TIL for two clinical trials for the treatment of metastatic melanoma at MD Anderson Cancer Center.
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- 2017
47. Parallel profiling of immune infiltrate subsets in uveal melanoma versus cutaneous melanoma unveils similarities and differences: A pilot study
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Cara Haymaker, Michelle D. Williams, Sapna Pradyuman Patel, Zachary A. Cooper, Mariana Petaccia de Macedo, Bita Esmaeli, Wei Lien Wang, Rodabe N. Amaria, Alexandre Reuben, Orenthial J. Fulbright, Arely Wahl, Sujan T Reddy, Alexander J. Lazar, Yong Qin, Renjith Ramachandran, Patrick Hwu, Vancheswaran Gopalakrishnan, Esteban Flores, Michael T. Tetzlaff, Claudius Conrad, Rene J. Tavera, Marie Andrée Forget, Chantale Bernatchez, Jennifer A. Wargo, Shawne T. Thorsen, Christine N. Spencer, and Dan S. Gombos
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Lymphocyte ,Immunology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Immunology and Allergy ,RC254-282 ,Immune infiltrate ,Tumor-infiltrating lymphocytes ,business.industry ,Brief Report ,Melanoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,immune profile ,Immunotherapy ,RC581-607 ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,tumor infiltrating lymphocytes ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,Immunohistochemistry ,Immunologic diseases. Allergy ,uveal melanoma ,business ,CD8 - Abstract
The low response rates to immunotherapy in uveal melanoma (UM) sharply contrast with reputable response rates in cutaneous melanoma (CM) patients. To characterize the mechanisms responsible for resistance to immunotherapy in UM, we performed immune profiling in tumors from 10 metastatic UM patients and 10 metastatic CM patients by immunohistochemistry (IHC). Although there is no difference in infiltrating CD8+ T cells between UM and CM, a significant decrease in programmed death-1 (PD-1)-positive lymphocytes was observed and lower levels of programmed death ligand-1 (PD-L1) in UM metastases compared with CM metastases. Tumors from metastatic UM patients showed a lower success rate of tumor-infiltrating lymphocyte (TIL) growth compared with metastatic CM (45% vs. 64% success), with a significantly lower quantity of UM TIL expanded overall. These studies suggest that UM and CM are immunologically distinct, and provide potential explanation for the impaired success of immunotherapy in UM.
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- 2017
48. 4-1BB–enhanced expansion of CD8+ TIL from triple-negative breast cancer unveils mutation-specific CD8+ T cells
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Gildy Babiera, Laszlo Radvanyi, Jessica Ann Chacon, Korrene F. Rockwood, Jason Roszik, Michiko Harao, James M. Reuben, EA Mittendorf, Cara Haymaker, Luis M Vence, Sarah M. DeSnyder, Naoto T. Ueno, Chantale Bernatchez, Shumin Li, Hui Gao, Marie Andrée Forget, and Savitri Krishnamurthy
- Subjects
0301 basic medicine ,Cancer Research ,Immunology ,chemical and pharmacologic phenomena ,Triple Negative Breast Neoplasms ,CD8-Positive T-Lymphocytes ,Article ,Cell therapy ,03 medical and health sciences ,Tumor Necrosis Factor Receptor Superfamily, Member 9 ,0302 clinical medicine ,Breast cancer ,Lymphocytes, Tumor-Infiltrating ,medicine ,Tumor Cells, Cultured ,Cytotoxic T cell ,Humans ,Triple-negative breast cancer ,business.industry ,Melanoma ,CD137 ,Cancer ,Antibodies, Monoclonal ,hemic and immune systems ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Female ,business ,CD8 - Abstract
Triple-negative breast cancer (TNBC) highly infiltrated with CD8+ tumor-infiltrating lymphocytes (TIL) has been associated with improved prognosis. This observation led us to hypothesize that CD8+ TIL could be utilized in autologous adoptive cell therapy for TNBC, although this concept has proven to be challenging, given the difficulty in expanding CD8+ TILs in solid cancers other than in melanoma. To overcome this obstacle, we used an agonistic antibody (urelumab) to a TNFR family member, 4-1BB/CD137, which is expressed by recently activated CD8+ T cells. This approach was first utilized in melanoma and, in this study, led to advantageous growth of TILs for the majority of TNBC tumors tested. The agonistic antibody was only added in the initial setting of the culture and yet favored the propagation of CD8+ TILs from TNBC tumors. These expanded CD8+ TILs were capable of cytotoxic functions and were successfully utilized to demonstrate the presence of immunogenic mutations in autologous TNBC tumor tissue without recognition of the wild-type counterpart. Our findings open the way for a successful adoptive immunotherapy for TNBC. Cancer Immunol Res; 5(6); 439–45. ©2017 AACR.
- Published
- 2017
49. Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma
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Haven R. Garber, Xingzhi Song, Padmanee Sharma, Alexandria P. Cogdill, Brett W. Carter, Robert Sloane, Jeffrey E. Gershenwald, Xizeng Mao, Zachary A. Cooper, Mariana Petaccia de Macedo, Christine N. Spencer, Jacob Austin-Breneman, Michael A. Davies, Jason Roszik, Ignacio I. Wistuba, Hannah C. Beird, P. Andrew Futreal, Karen Clise-Dwyer, Rodabe N. Amaria, Peter A. Prieto, Curtis Gumbs, James P. Allison, Hong Jiang, Alexandre Reuben, Luigi Nezi, Alexander J. Lazar, Cara Haymaker, Jianhua Hu, Jianhua Zhang, Sapna Pradyuman Patel, Adi Diab, Sangeetha M. Reddy, Rebecca Thornton, Elizabeth A. Grimm, Scott E. Woodman, Latasha Little, Hussein Abdul-Hassan Tawbi, Courtney W. Hudgens, Marie Andrée Forget, Patrick Hwu, Pei Ling Chen, Michael T. Tetzlaff, Jiong Chen, Wei Shen Chen, Isabella C. Glitza, Lynda Chin, Chantale Bernatchez, Jennifer A. Wargo, Jeffrey E. Lee, Vancheswaran Gopalakrishnan, Khalida Wani, Eveline Chen, John P. Miller, and Whijae Roh
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,T cell ,medicine.medical_treatment ,QH426-470 ,Article ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,Genetics ,Medicine ,Molecular Biology ,Genetics (clinical) ,business.industry ,Melanoma ,Cancer ,Precision medicine ,medicine.disease ,Immune checkpoint ,3. Good health ,Blockade ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,business - Abstract
Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (, Melanoma: Tumor differences within a patient may explain heterogeneous responses Patients with metastatic melanoma display molecular and immune differences across tumor sites associated with differential drug responses. A team led by Jennifer Wargo from the University of Texas MD Anderson Cancer Center, Houston, USA, studied the radiological responses of 60 patients with metastatic melanoma, half of whom received targeted drug therapy and half of whom received an immune checkpoint inhibitor. The majority (83%) showed differences in responses across metastases. The group then profiled tumors in a subset, and found molecular and immune heterogeneity in different tumors within the same patient. Heterogeneity in mutational and immune profiles within tumors from individual patients could explain differences in treatment response. Knowing this, the authors emphasize the importance of acquiring biopsies from more than one tumor site in order to best tailor therapies to the features of metastatic cancer.
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- 2017
50. Erratum to: A case report of Grover’s disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1
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Elizabeth Sirmans, Faisal Fa’ak, Courtney W. Hudgens, Lydia Barbara, Marc Uemura, Cara Haymaker, Adi Diab, Chantale Bernatchez, Natalie McQuail, Patrick Hwu, Michael T. Tetzlaff, and Jonathan L. Curry
- Subjects
Pharmacology ,Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cancer ,Case Report ,Immunotherapy ,medicine.disease ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Skin toxicity ,Oncology ,CTLA-4 ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Erratum ,Grover's disease ,business - Abstract
Background Immune related adverse events (irAEs) are common side effects of checkpoint inhibitory (CPI) therapies targeting CTLA-4 and PD-1/PD-L1. Grover’s disease is an uncommon dermatologic condition with unclear pathogenesis previously reported as an irAE with ipilimumab. Case Presentation We report an additional case of ipilimumab-induced Grover’s disease. Interestingly, this dermatologic side effect did not appear with use of anti-PD-1 therapy in our patient. Immune analysis was performed and suggests a possible role of Th2 cells in its patholgenesis. Conclusion This case suggests that Grover's disease is an irAE induced by Ipilimumab. Our immune analysis suggests that Th2 cells may be pathogenic mediators which warrants further study.
- Published
- 2017
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