350 results on '"Chantale Bernatchez"'
Search Results
102. Supplementary Table 5 from Pilot Clinical Trial of Perioperative Durvalumab and Tremelimumab in the Treatment of Resectable Colorectal Cancer Liver Metastases
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Michael J. Overman, Jean-Nicolas Vauthey, Scott Kopetz, Chantale Bernatchez, Alda Tam, Robert Jenq, Chia-Chi Chang, Van Morris, Kanwal Raghav, Christine Parseghian, Ching-Wei Tzeng, Luisa Solis, David Menter, Bryan Kee, Andy Futreal, Yun Shin Chun, Dipen M. Maru, Wai Chin Foo, Xiaofei Song, Rebecca S. Slack Tidwell, Ignacio I. Wistuba, Daniele Lorenzini, Swati Gite, Rossana Lazcano, Young Uk Kim, Edwin Roger Parra, Cara Haymaker, and Preeti Kanikarla Marie
- Abstract
RFS long and short microbiome-taxa abundance
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- 2023
103. Supplementary Figure 5 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
- Abstract
Detection of HVEM expression by flow cytometry in B16 OVA or B16 F10 cell lines.
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- 2023
104. Supplementary Tables from Elucidation of Tumor-Stromal Heterogeneity and the Ligand-Receptor Interactome by Single-Cell Transcriptomics in Real-world Pancreatic Cancer Biopsies
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Paola A. Guerrero, Anirban Maitra, Cullen M. Taniguchi, Chantale Bernatchez, Cara L. Haymaker, Manoop S. Bhutani, Brian R. Weston, Kimal I. Rajapakshe, Daniel Lin, Bret M. Stephens, Jonathan Huang, Maria E. Monberg, Alexander Semaan, Vincent Bernard, and Jaewon J. Lee
- Abstract
Tables
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- 2023
105. Supplementary Figures 1 - 7 from A New Approach to Simultaneously Quantify Both TCR α- and β-Chain Diversity after Adoptive Immunotherapy
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Laurence J.N. Cooper, Laszlo Radvanyi, Patrick Hwu, Luis M. Vence, Richard E. Champlin, Brian Rabinovich, Helen Huls, Chantale Bernatchez, Sourindra Maiti, and Minying Zhang
- Abstract
PDF file, 264K, Supplementary Fig. S1. TCR Va and Vb gene expression in total RNA from TILs patient 303 and patient 232. Supplementary Fig S2. Global measurement of TCR Va (A-C) and TCR Vb (D-F) gene expression in patient 231 including in vitro rapid expanded TIL (A and D) and PBMC (B-C and E-F) collected after TIL infusion. Supplementary Fig S3. Global measurement of TCR Va (A-D) and TCR Vb (E-H) gene expression in patient 228 including in vitro rapid expanded TIL (A and E) and PBMC (B-D) and (F-H) collected after TIL infusion. Supplementary Fig S4. Global measurement of TCR Va (A-D) and TCR Vb (E-H) gene expression in patient 106 including in vitro rapid expanded TIL (A and E) and PBMC (B-D) and (F-H) collected after TIL infusion. Supplementary Fig S5. Global measurement of TCR Va (A-D) and TCR Vb (E-H) gene expression in patient 172 including in vitro rapid expanded TIL (A and E) and PBMC (B-D) and (F-H) collected after TIL infusion. Supplementary Fig S6. Global measurement of TCR Va (A-D) and TCR Vb (E-H) gene expression in patient 152 including in vitro rapid expanded TIL (A and E) and PBMC (B-D) and (F-H) collected after TIL infusion. Supplementary Fig S7. Global measurement of TCR Va (A-D) and TCR Vb (E-H) gene expression in patient 188 including in vitro rapid expanded TIL (A and E) and PBMC (B-D) and (F-H) collected after TIL infusion.
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- 2023
106. Movie 3 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
- Abstract
Movie 3 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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- 2023
107. Supplementary Table 2 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
- Abstract
Modifications to the BTLA sequence introduced to generate the variants used in this study are shown in red.
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- 2023
108. Supplementary Figure and Supplementary Tables from 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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Chantale Bernatchez, Rodabe N. Amaria, Patrick Hwu, Rameen Beroukhim, Carlos A. Torres-Cabala, Laszlo G. Radvanyi, Jennifer A. Wargo, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Suzanne Cain, Michael K. Wong, Hussein Tawbi, Isabella C. Glitza, Adi Diab, Michael A. Davies, Sapna P. Patel, Wen-Jen Hwu, Portia G. Velasquez, Chantell M. Farinas, Carol Vaughn, Destiny Joy Carpio, Vruti Patel, Rahmatu Mansaray, Seth Wardell, Christopher L. Toth, Audrey M. Gonzalez, Renjith Ramachandran, René J. Tavera, Shawne T. Thorsen, Esteban Flores, Arely Wahl, Ankit Bhatta, Donastas Sakellariou-Thompson, Young Uk Kim, Scott E. Woodman, Jason Roszik, Orenthial J. Fulbright, Tatiana Karpinets, Caitlin Creasy, Yuzhong Jeff Meng, Kenneth R. Hess, Cara Haymaker, and Marie-Andrée Forget
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Supplementary figures and tables
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- 2023
109. Data from T-cell Homing Therapy for Reducing Regulatory T Cells and Preserving Effector T-cell Function in Large Solid Tumors
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Shulin Li, Gianpietro Dotti, Patrick Hwu, Xueqing Xia, Chantale Bernatchez, Chuang Sun, and Jiemiao Hu
- Abstract
Purpose: Infused autologous tumor-infiltrating lymphocytes (TIL) and tumor-targeted chimeric antigen receptor (CAR) T cells typically surround malignant lesions or penetrate small tumor nodules but fail to penetrate large solid tumors, significantly compromising their antitumor impact. Strategies to overcome this primary challenge are largely required.Experimental Design: We tested the effects of IL12 plus doxorubicin on T-cell penetration and efficacy in solid tumors in a murine lung cancer model, a murine breast carcinoma lung metastasis model, and two human xenograft tumor models bearing large tumors (>10 mm).Results: Intriguingly, this simple approach increased the numbers, the distribution, and the depth of penetration of infused CD8+ T cells in these tumors, including both TILs and CAR T cells. This combined treatment halted tumor progression and significantly extended survival time. Studies of the underlying mechanism revealed multiple effects. First, the combined treatment maintained the high ratios of immune-stimulatory receptors to immune-inhibitory receptors on infiltrated CD8+ T cells, reduced the accumulation of immunosuppressive regulatory T cells, and enhanced the numbers of T-bet+ effector T cells in the tumors. Second, doxorubicin induced chemokines CXCL9 and CXCL10, which may attract NKG2D+CD8+ T cells to tumors, and this effect was boosted by IL12-induced IFNγ accumulation in tumors, promoting the penetration of NKG2D+CD8+ T cells.Conclusions: The deep penetration of infused T cells associated with combined IL12 plus doxorubicin yielded striking therapeutic effects in murine and human xenograft solid tumors. This approach might broaden the application of T-cell therapy to a wider range of solid tumors. Clin Cancer Res; 24(12); 2920–34. ©2018 AACR.See related commentary by Berraondo et al., p. 2716
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- 2023
110. Supplementary Table 2 from Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients
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Patrick Hwu, Audrey Gonzalez, Seth Wardell, Renjith Ramachandran, Christopher Toth, Orenthial J. Fulbright, Rahmatu Mansaray, Michael A. Davies, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Sapna Patel, Wen-Jen Hwu, Agop Bedikian, Jade Homsi, Kevin Kim, Nicholas Papadopoulos, Victor Prieto, Elizabeth Shpall, John D. McMannis, Valen E. Johnson, Michelle Glass, Gladys Alvarado, Sandy Mahoney, Gregory Lizee, Richard Wu, Jessica Chacon, Priscilla Miller, Patricia S. Fox, Minying Zhang, Chantale Bernatchez, and Laszlo G. Radvanyi
- Abstract
PDF file - 69K, Derivation of the irRC best overall score
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- 2023
111. Supplementary methods and data from 4-1BB Agonist Focuses CD8+ Tumor-Infiltrating T-Cell Growth into a Distinct Repertoire Capable of Tumor Recognition in Pancreatic Cancer
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Chantale Bernatchez, Cara Haymaker, Anirban Maitra, Patrick Hwu, Jianhua Zhang, Timothy P. Heffernan, Hector A. Alvarez, Michael J. Overman, Milind Javle, Gauri Varadhachary, Jason B. Fleming, Jaime Rodriguez-Canales, Christopher A. Bristow, Ya'an Kang, Edwin Roger Parra, Naohiro Uraoka, Mark W. Hurd, Young Uk Kim, Li Zhao, Vincent Bernard, Caitlin Creasy, Marie-Andrée Forget, and Donastas Sakellariou-Thompson
- Abstract
Supplementary material and method Supplementary Figure S1. Addition of a4-1BB does not lead CD8+ TIL into senescence. Supplementary Figure S2. Fold expansion of bulk and CD8+ PDAC TIL following the REP. Supplementary Figure S3. Level of MHC class I expression on PDAC tumor cell lines.
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- 2023
112. Supplementary Table S1 from The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression
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Patrick Hwu, Scott E. Woodman, Gregory Lizée, Jason Roszik, Weiyi Peng, Anil Korkut, Rodabe N. Amaria, Timothy Heffernan, Chantale Bernatchez, Michael A. Davies, Jennifer A. Wargo, Roger S. Lo, Richard Eric Davis, Zhi-Qiang Wang, Rina M. Mbofung, Zhe Wang, Leila J. Williams, Marie-Andrée Forget, Cara Haymaker, Tatiana Karpinets, Trang Tieu, Amjad H. Talukder, Miles C. Andrews, Jodi A. McKenzie, Shruti Malu, and Lu Huang
- Abstract
A list of all 384 ORFs in the library
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- 2023
113. Supplementary Methods from Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients
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Patrick Hwu, Audrey Gonzalez, Seth Wardell, Renjith Ramachandran, Christopher Toth, Orenthial J. Fulbright, Rahmatu Mansaray, Michael A. Davies, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Sapna Patel, Wen-Jen Hwu, Agop Bedikian, Jade Homsi, Kevin Kim, Nicholas Papadopoulos, Victor Prieto, Elizabeth Shpall, John D. McMannis, Valen E. Johnson, Michelle Glass, Gladys Alvarado, Sandy Mahoney, Gregory Lizee, Richard Wu, Jessica Chacon, Priscilla Miller, Patricia S. Fox, Minying Zhang, Chantale Bernatchez, and Laszlo G. Radvanyi
- Abstract
PDF file - 115K
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- 2023
114. Supplementary Figure 1 from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma
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Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili
- Abstract
PDF file, 473K, (A) Frequencies of IL-1α and IL-1β staining at different disease stages. Sections of a melanoma progression tissue array stained with antibodies specific for IL-1α or IL-1β and visualized by Vector-red immunostaining. Red color indicates positive staining for (C-E) IL-1α or (G-I) IL-1β in representative primary and metastatic tumors. (J) IL-1α or (K) IL-1β from stage 3 lymph node metastasis of tumors with (red) or without (black) the BRAF V600E mutation. Scores indicates the product of the intensity of signal (0-3) and frequency (0-100) of immunoreactive cells. (L) Presence or absence of IL-1α or IL-1β in melanoma cell lines with known BRAF mutational status. Asterisks, in house, or references (ref.) indicate the source of mutational analysis, (first) and the source of the IL-1 analysis (first and last respectively). Methods of BRAF mutational analysis are indicated by P, pyrosequencing; S, Sanger sequencing; Q, sequenome. Bold text indicates cell lines used in this study.
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- 2023
115. Data from The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression
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Patrick Hwu, Scott E. Woodman, Gregory Lizée, Jason Roszik, Weiyi Peng, Anil Korkut, Rodabe N. Amaria, Timothy Heffernan, Chantale Bernatchez, Michael A. Davies, Jennifer A. Wargo, Roger S. Lo, Richard Eric Davis, Zhi-Qiang Wang, Rina M. Mbofung, Zhe Wang, Leila J. Williams, Marie-Andrée Forget, Cara Haymaker, Tatiana Karpinets, Trang Tieu, Amjad H. Talukder, Miles C. Andrews, Jodi A. McKenzie, Shruti Malu, and Lu Huang
- Abstract
Purpose: Cancer immunotherapy has shown promising clinical outcomes in many patients. However, some patients still fail to respond, and new strategies are needed to overcome resistance. The purpose of this study was to identify novel genes and understand the mechanisms that confer resistance to cancer immunotherapy.Experimental Design: To identify genes mediating resistance to T-cell killing, we performed an open reading frame (ORF) screen of a kinome library to study whether overexpression of a gene in patient-derived melanoma cells could inhibit their susceptibility to killing by autologous tumor-infiltrating lymphocytes (TIL).Results: The RNA-binding protein MEX3B was identified as a top candidate that decreased the susceptibility of melanoma cells to killing by TILs. Further analyses of anti–PD-1–treated melanoma patient tumor samples suggested that higher MEX3B expression is associated with resistance to PD-1 blockade. In addition, significantly decreased levels of IFNγ were secreted from TILs incubated with MEX3B-overexpressing tumor cells. Interestingly, this phenotype was rescued upon overexpression of exogenous HLA-A2. Consistent with this, we observed decreased HLA-A expression in MEX3B-overexpressing tumor cells. Finally, luciferase reporter assays and RNA-binding protein immunoprecipitation assays suggest that this is due to MEX3B binding to the 3′ untranslated region (UTR) of HLA-A to destabilize the mRNA.Conclusions: MEX3B mediates resistance to cancer immunotherapy by binding to the 3′ UTR of HLA-A to destabilize the HLA-A mRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells. Clin Cancer Res; 24(14); 3366–76. ©2018 AACR.See related commentary by Kalbasi and Ribas, p. 3239
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- 2023
116. Supplementary Figure 5 from Elucidation of Tumor-Stromal Heterogeneity and the Ligand-Receptor Interactome by Single-Cell Transcriptomics in Real-world Pancreatic Cancer Biopsies
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Paola A. Guerrero, Anirban Maitra, Cullen M. Taniguchi, Chantale Bernatchez, Cara L. Haymaker, Manoop S. Bhutani, Brian R. Weston, Kimal I. Rajapakshe, Daniel Lin, Bret M. Stephens, Jonathan Huang, Maria E. Monberg, Alexander Semaan, Vincent Bernard, and Jaewon J. Lee
- Abstract
Figure
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- 2023
117. Supplementary Table 1 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
- Abstract
Sequence of the primers used to amplify mouse BTLA
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- 2023
118. Data from 4-1BB Agonist Focuses CD8+ Tumor-Infiltrating T-Cell Growth into a Distinct Repertoire Capable of Tumor Recognition in Pancreatic Cancer
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Chantale Bernatchez, Cara Haymaker, Anirban Maitra, Patrick Hwu, Jianhua Zhang, Timothy P. Heffernan, Hector A. Alvarez, Michael J. Overman, Milind Javle, Gauri Varadhachary, Jason B. Fleming, Jaime Rodriguez-Canales, Christopher A. Bristow, Ya'an Kang, Edwin Roger Parra, Naohiro Uraoka, Mark W. Hurd, Young Uk Kim, Li Zhao, Vincent Bernard, Caitlin Creasy, Marie-Andrée Forget, and Donastas Sakellariou-Thompson
- Abstract
Purpose: Survival for pancreatic ductal adenocarcinoma (PDAC) patients is extremely poor and improved therapies are urgently needed. Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) has shown great promise in other tumor types, such as metastatic melanoma where overall response rates of 50% have been seen. Given this success and the evidence showing that T-cell presence positively correlates with overall survival in PDAC, we sought to enrich for CD8+ TILs capable of autologous tumor recognition. In addition, we explored the phenotype and T-cell receptor repertoire of the CD8+ TILs in the tumor microenvironment.Experimental Design: We used an agonistic 4-1BB mAb during the initial tumor fragment culture to provide 4-1BB costimulation and assessed changes in TIL growth, phenotype, repertoire, and antitumor function.Results: Increased CD8+ TIL growth from PDAC tumors was achieved with the aid of an agonistic 4-1BB mAb. Expanded TILs were characterized by an activated but not terminally differentiated phenotype. Moreover, 4-1BB stimulation expanded a more clonal and distinct CD8+ TIL repertoire than IL2 alone. TILs from both culture conditions displayed MHC class I-restricted recognition of autologous tumor targets.Conclusions: Costimulation with an anti-4-1BB mAb increases the feasibility of TIL therapy by producing greater numbers of these tumor-reactive T cells. These results suggest that TIL ACT for PDAC is a potential treatment avenue worth further investigation for a patient population in dire need of improved therapy. Clin Cancer Res; 23(23); 7263–75. ©2017 AACR.
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- 2023
119. Supplementary Figure 7 from Elucidation of Tumor-Stromal Heterogeneity and the Ligand-Receptor Interactome by Single-Cell Transcriptomics in Real-world Pancreatic Cancer Biopsies
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Paola A. Guerrero, Anirban Maitra, Cullen M. Taniguchi, Chantale Bernatchez, Cara L. Haymaker, Manoop S. Bhutani, Brian R. Weston, Kimal I. Rajapakshe, Daniel Lin, Bret M. Stephens, Jonathan Huang, Maria E. Monberg, Alexander Semaan, Vincent Bernard, and Jaewon J. Lee
- Abstract
supplementary figure
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- 2023
120. Supplementary Table 1 and 2 from Pilot Clinical Trial of Perioperative Durvalumab and Tremelimumab in the Treatment of Resectable Colorectal Cancer Liver Metastases
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Michael J. Overman, Jean-Nicolas Vauthey, Scott Kopetz, Chantale Bernatchez, Alda Tam, Robert Jenq, Chia-Chi Chang, Van Morris, Kanwal Raghav, Christine Parseghian, Ching-Wei Tzeng, Luisa Solis, David Menter, Bryan Kee, Andy Futreal, Yun Shin Chun, Dipen M. Maru, Wai Chin Foo, Xiaofei Song, Rebecca S. Slack Tidwell, Ignacio I. Wistuba, Daniele Lorenzini, Swati Gite, Rossana Lazcano, Young Uk Kim, Edwin Roger Parra, Cara Haymaker, and Preeti Kanikarla Marie
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Treatment related adverse events and list of antibodies used.
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- 2023
121. Movie 1 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
- Abstract
Movie 1 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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- 2023
122. Supplementary Figure 3 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
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Expression of BTLA in human CD8+ T cells according to differentiation status.
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- 2023
123. Supplementary Table 3 - 4 from Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients
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Patrick Hwu, Audrey Gonzalez, Seth Wardell, Renjith Ramachandran, Christopher Toth, Orenthial J. Fulbright, Rahmatu Mansaray, Michael A. Davies, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Sapna Patel, Wen-Jen Hwu, Agop Bedikian, Jade Homsi, Kevin Kim, Nicholas Papadopoulos, Victor Prieto, Elizabeth Shpall, John D. McMannis, Valen E. Johnson, Michelle Glass, Gladys Alvarado, Sandy Mahoney, Gregory Lizee, Richard Wu, Jessica Chacon, Priscilla Miller, Patricia S. Fox, Minying Zhang, Chantale Bernatchez, and Laszlo G. Radvanyi
- Abstract
PDF file - 76k, Table S3. Associations between categorical patient variables and clinical response; Table S4. Associations between continuous variables and clinical response
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- 2023
124. Supplementary Figure 2 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
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Expression of BTLA in murine CD8+ T cells according to differentiation status.
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- 2023
125. Supplementary Table 3 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
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Reverse Phase Protein Array (RPPA) data of either mouse T cells or human CD8+ Tumor Infiltrating Lymphocytes stimulated with anti-CD3 with or without HVEM-FC.
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- 2023
126. Supplementary Figure 6 from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma
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Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili
- Abstract
PDF file, 99K, Four separate TAF lines were derived from human melanoma tumor biopsies and exposed overnight to recombinant human IL-1α (1 ng/ml) or IFN-γ (500 U/ml). TAFs were then stained using antibodies specific for PD-L1 and PD-L2, and analyzed for surface expression by flow cytometry.
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- 2023
127. Supplementary information from The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression
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Patrick Hwu, Scott E. Woodman, Gregory Lizée, Jason Roszik, Weiyi Peng, Anil Korkut, Rodabe N. Amaria, Timothy Heffernan, Chantale Bernatchez, Michael A. Davies, Jennifer A. Wargo, Roger S. Lo, Richard Eric Davis, Zhi-Qiang Wang, Rina M. Mbofung, Zhe Wang, Leila J. Williams, Marie-Andrée Forget, Cara Haymaker, Tatiana Karpinets, Trang Tieu, Amjad H. Talukder, Miles C. Andrews, Jodi A. McKenzie, Shruti Malu, and Lu Huang
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Supplementary figure and table legends
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- 2023
128. Supplementary Table 5 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
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RPPA data of human CD8+ TIL (N=5) stimulated with anti-CD3 with or without HVEM-FC
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- 2023
129. Supplement Figures S1-S4 from T-cell Homing Therapy for Reducing Regulatory T Cells and Preserving Effector T-cell Function in Large Solid Tumors
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Shulin Li, Gianpietro Dotti, Patrick Hwu, Xueqing Xia, Chantale Bernatchez, Chuang Sun, and Jiemiao Hu
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Fig. S1. CD4+ T cell infiltration in mouse and human tumor sections. Fig. S2. Correlations between the numbers of infiltrated murine T cells and the ratios of costimulatory and coinhibitory receptors. Fig. S3. Quantitative PCR analysis of CXCL9 and CXCL10 mRNA expression in tumor cells that were treated with doxorubicin. Fig. S4. Induction of CXCL9 and CXCL10 at mRNA levels in LLC and Mel2549 tumors after the treatment with IL-12 plus doxorubicin plus T cell infusion.
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- 2023
130. Supplementary Figure 1 from Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
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Chantale Bernatchez, Patrick Hwu, Laszlo G. Radvanyi, Roza Nurieva, Navin Varadarajan, Willem W. Overwijk, Yared Hailemichael, Jason Roszik, Luis M. Vence, Charuta Kale, Minying Zhang, Xiaohui Yi, Andrew Aschenbrenner, Melisa Martinez, Cara L. Haymaker, and Krit Ritthipichai
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Analysis of the expression of CD8 and BTLA at the RNA level in data from melanoma patients in TCGA.
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- 2023
131. Obesity is associated with altered tumor metabolism in metastatic melanoma
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Andrew W. Hahn, Ashley V. Menk, Dayana B. Rivadeneira, Ryan C. Augustin, Mingchu Xu, Jun Li, Xiaogang Wu, Aditya K. Mishra, Tuba N. Gide, Camelia Quek, Yan Zang, Christine N. Spencer, Alexander M. Menzies, Carrie R. Daniel, Courtney W. Hudgens, Theodore Nowicki, Lauren E. Haydu, M.A. Wadud Khan, Vancheswaran Gopalakrishnan, Elizabeth M. Burton, Jared Malke, Julie M. Simon, Chantale Bernatchez, Nagireddy Putluri, Scott E. Woodman, Y.N. Vashisht Gopal, Renato Guerrieri, Grant M. Fischer, Jian Wang, Khalida M. Wani, John F. Thompson, Jeffrey E. Lee, Patrick Hwu, Nadim Ajami, Jeffrey E. Gershenwald, Georgina V. Long, Richard A. Scolyer, Michael T. Tetzlaff, Alexander J. Lazar, Dirk Schadendorf, Jennifer A. Wargo, John M. Kirkwood, Ralph J. DeBerardinis, Han Liang, Andrew Futreal, Jianhua Zhang, James S. Wilmott, Weiyi Peng, Michael A. Davies, Greg M. Delgoffe, Yana G. Najjar, and Jennifer L. McQuade
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Cancer Research ,Oncology ,Humans ,Neoplasms, Second Primary ,Obesity ,Overweight ,Melanoma ,Article - Abstract
Purpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Experimental Design: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371). Results: DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI. Conclusions: These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies. See related commentary by Smalley, p. 5
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- 2023
132. Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma
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Caitlin A. Creasy, Yuzhong Jeff Meng, Marie-Andrée Forget, Tatiana Karpinets, Katarzyna Tomczak, Chip Stewart, Carlos A. Torres-Cabala, Shari Pilon-Thomas, Amod A. Sarnaik, James J. Mulé, Levi Garraway, Matias Bustos, Jianhua Zhang, Sapna P. Patel, Adi Diab, Isabella C. Glitza, Cassian Yee, Hussein Tawbi, Michael K. Wong, Jennifer McQuade, Dave S.B. Hoon, Michael A. Davies, Patrick Hwu, Rodabe N. Amaria, Cara Haymaker, Rameen Beroukhim, and Chantale Bernatchez
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Cancer Research ,Lymphocytes, Tumor-Infiltrating ,Oncology ,Cell- and Tissue-Based Therapy ,Tumor Microenvironment ,Endothelial Cells ,Humans ,Neoplasms, Second Primary ,Genomics ,Immunotherapy, Adoptive ,Melanoma ,Article - Abstract
Purpose:Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%–50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.Experimental Design:We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.Results:Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved PFS and OS. In contrast, the expression of ELFN1 was enriched in patients with unfavorable response, poor PFS and OS, whereas enhanced methylation of ELFN1 was observed in patients with favorable outcomes. Expression of ELFN1, NGFR, and PDE1C was mainly found in cancer-associated fibroblasts and endothelial cells in tumor tissues across different cancer types in publicly available single-cell RNA sequencing datasets, suggesting a role for elements of the tumor microenvironment in defining the outcome of TIL therapy.Conclusions:Our findings suggest that transcriptional features of melanomas correlate with outcomes after TIL therapy and may provide candidates to guide patient selection.
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- 2022
133. 782 Intratumoral sotigalimab with pembrolizumab activates antigen-presenting cells and induces local and distant anti-tumor responses in first-line metastatic melanoma: results of a phase I/II study
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Salah-Eddine Bentebibel, Daniel Johnson, Barbara Pazdrak, Daniel McGrail, Srisuda Lecagoonporn, Cara Haymaker, Dzifa Y Duose, Khalida Wani, Heather Sonnemann, Houssein Safa, Jared K Burks, Patrick Hwu, cho Sungnam, Chantale Bernatchez, Suhendan Ekmekcioglu, Gregory Lizée, and Adi Diab
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- 2022
134. Single cell sequencing reveals trajectory of tumor-infiltrating lymphocyte states in pancreatic cancer
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Aislyn Schalck, Donastas Sakellariou-Thompson, Marie-Andrée Forget, Emi Sei, Tara G. Hughes, Alexandre Reuben, Shanshan Bai, Min Hu, Tapsi Kumar, Mark W. Hurd, Matthew H.G. Katz, Ching-Wei D. Tzeng, Shubham Pant, Milind Javle, David R. Fogelman, Anirban Maitra, Cara L. Haymaker, Michael P. Kim, Nicholas E. Navin, and Chantale Bernatchez
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Pancreatic Neoplasms ,Lymphocytes, Tumor-Infiltrating ,Oncology ,Receptors, Antigen, T-Cell ,Humans ,Article ,Carcinoma, Pancreatic Ductal - Abstract
Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distributions of TIL populations. The CD8+ TIL contained a putative transitional GZMK+ population based on T-cell receptor clonotype sharing, and cell-state trajectory analysis showed similarity to a GZMB+PRF1+ cytotoxic and a CXCL13+ dysfunctional population. Statistical analysis suggested that certain TIL states, such as dysfunctional and inhibitory populations, often occurred together. Finally, analysis of cultured TIL revealed that high-frequency clones from effector populations were preferentially expanded. These data provide a framework for understanding the PDAC TIL landscape for future TIL use in immunotherapy for PDAC. Significance: To improve the efficacy of immunotherapy in PDAC, there is a great need to understand the PDAC TIL landscape. This study represents a reference of PDAC TIL subpopulations and their relationships and provides a foundation upon which to base future immunotherapeutic efforts. This article is highlighted in the In This Issue feature, p. 2221
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- 2022
135. Deep learning-based prediction of the T cell receptor–antigen binding specificity
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Tao Wang, Ze Zhang, Tianshi Lu, Lin Xu, John V. Heymach, Don L. Gibbons, Peixin Jiang, James Zhu, Alexandre Reuben, Xue Xiao, Jun Wang, Yunguan Wang, and Chantale Bernatchez
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integumentary system ,Computer Networks and Communications ,medicine.medical_treatment ,Melanoma ,T cell ,T-cell receptor ,chemical and pharmacologic phenomena ,Immunotherapy ,Computational biology ,Biology ,medicine.disease ,Major histocompatibility complex ,Article ,Human-Computer Interaction ,medicine.anatomical_structure ,Antigen ,Artificial Intelligence ,medicine ,biology.protein ,Computer Vision and Pattern Recognition ,Allele ,Receptor ,Software - Abstract
Neoantigens play a key role in the recognition of tumour cells by T cells; however, only a small proportion of neoantigens truly elicit T-cell responses, and few clues exist as to which neoantigens are recognized by which T-cell receptors (TCRs). We built a transfer learning-based model named the pMHC–TCR binding prediction network (pMTnet) to predict TCR binding specificities of the neoantigens—and T cell antigens in general—presented by class I major histocompatibility complexes. pMTnet was comprehensively validated by a series of analyses and exhibited great advances over previous works. By applying pMTnet to human tumour genomics data, we discovered that neoantigens were generally more immunogenic than self-antigens, but human endogenous retrovirus E (a special type of self-antigen that is reactivated in kidney cancer) is more immunogenic than neoantigens. We further discovered that patients with more clonally expanded T cells that exhibit better affinity against truncal rather than subclonal neoantigens had more favourable prognosis and treatment response to immunotherapy in melanoma and lung cancer but not in kidney cancer. Predicting TCR–neoantigen/antigen pairing is one of the most daunting challenges in modern immunology; however, we achieved an accurate prediction of the pairing using only the TCR sequence (CDR3β), antigen sequence and class I major histocompatibility complex allele, and our work revealed unique insights into the interactions between TCRs and major histocompatibility complexes in human tumours, using pMTnet as a discovery tool. T-cell immunity is driven by the interaction between peptides presented by major histocompatibility complexes (pMHCs) and T-cell receptors (TCRs). Only a small proportion of neoantigens elicit T-cell responses, and it is not clear which neoantigens are recognized by which TCRs. The authors develop a transfer learning model to predict TCR binding specificity to class-I pMHCs.
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- 2021
136. Elucidation of Tumor-Stromal Heterogeneity and the Ligand-Receptor Interactome by Single-Cell Transcriptomics in Real-world Pancreatic Cancer Biopsies
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Bret M. Stephens, Maria E. Monberg, Vincent Bernard, Kimal I. Rajapakshe, Manoop S. Bhutani, Chantale Bernatchez, Jaewon J. Lee, Daniel Lin, Cullen M. Taniguchi, Jonathan Huang, Cara Haymaker, Alexander Semaan, Brian Weston, Paola A. Guerrero, and Anirban Maitra
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Cancer Research ,Tumor microenvironment ,Stromal cell ,endocrine system diseases ,Biopsy ,medicine.medical_treatment ,Context (language use) ,Immunotherapy ,Biology ,Precision medicine ,medicine.disease ,Interactome ,Article ,Pancreatic Neoplasms ,Transcriptome ,Oncology ,Pancreatic cancer ,Exome Sequencing ,Tumor Microenvironment ,Cancer research ,medicine ,Humans ,Carcinoma, Pancreatic Ductal - Abstract
Purpose: Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. With molecular subtypes of PDAC gaining relevance in the context of therapeutic stratification, the ability to characterize heterogeneity of cancer-specific gene expression patterns is of great interest. In addition, understanding patterns of immune evasion within PDAC is of importance as novel immunotherapeutic strategies are developed. Experimental Design: Single-cell RNA sequencing (scRNA-seq) is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes. Results: Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast subclasses, and predicts for a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches. Conclusions: Our analysis demonstrates that the use of de novo biopsies from patients with PDAC paired with scRNA-seq may facilitate therapeutic prediction from limited biopsy samples.
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- 2021
137. Metabolic plasticity of T-cell therapies: multi-omic profiling of interacting human tumor-infiltrating lymphocytes and autologous tumor adoptive cell therapy
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Melisa Martinez-Paniagua, Cara Haymaker, Jonathan Robinson, Michal Harel, Caitlin Creasy, Jay R T. Adolacion, Xingyue An, Mohsen Fathi, Ali Rezvan, Monish Kumar, Amit Amritkar, Scott E. Woodman, Rodabe N. Amaria, Tamar Geiger, Patrick Hwu, Chantale Bernatchez, and Navin Varadarajan
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Adoptive cell therapy (ACT) based on ex vivo expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate durable antitumor responses even in heavily pretreated patients. However, only a subset of patients responds to ACT; efforts to identify correlates of response have focused on profiling the tumor or the TIL but rarely in an interactive environment. Interactive profiling can provide unique insights into the clinical performance of TILs since the fate, function, and metabolism of TILs are influenced by autologous tumor-derived factors. Here, we performed a suite of cell-sparing assays dubbed holistic analysis of the bioactivity of interacting T cells and autologous tumor cells (HABITAT). HABITAT profiling of TILs used for human ACT and their autologous tumor cells included function-based single-cell profiling by timelapse imaging microscopy in nanowell grids (TIMING); multi-omics using RNA-sequencing and proteomics; metabolite inference using genome-scale metabolic modeling, and pulse-chase assays based on confocal microscopy to profile the uptake and fate of fatty acids (FA). Phenotypically, the ACT TILs from both responders (Rs) and nonresponders (NRs) were comprised of predominantly effector memory T cells (TEM cells) and did not express a high frequency of programmed death ligand-1 (PD-L1) and showed no differences in TCR diversity. Our results demonstrate that while tumor cells from both Rs and NRs are efficient at uptaking FAs, R TILs are significantly more efficient at utilizing FA through fatty acid oxidation (FAO) than NR TILs under nutrient starvation conditions. While it is likely that lipid and FA uptake is an inherent adaptation of TIL populations to lipid-rich environments, performing FAO sustains the survival of TILs and allows them to sustain antitumor cytolytic activity. We propose that metabolic plasticity enabling FAO is a desirable attribute of human TILs for ACT leading to clinical responses.
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- 2022
138. Single-cell CRISPR immune screens reveal immunological roles of tumor intrinsic factors
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Jiakai Hou, Shaoheng Liang, Chunyu Xu, Yanjun Wei, Yunfei Wang, Yukun Tan, Nidhi Sahni, Daniel J McGrail, Chantale Bernatchez, Michael Davies, Yumei Li, Rui Chen, S Stephen Yi, Yiwen Chen, Cassian Yee, Ken Chen, and Weiyi Peng
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General Medicine - Abstract
Genetic screens are widely exploited to develop novel therapeutic approaches for cancer treatment. With recent advances in single-cell technology, single-cell CRISPR screen (scCRISPR) platforms provide opportunities for target validation and mechanistic studies in a high-throughput manner. Here, we aim to establish scCRISPR platforms which are suitable for immune-related screens involving multiple cell types. We integrated two scCRISPR platforms, namely Perturb-seq and CROP-seq, with both in vitro and in vivo immune screens. By leveraging previously generated resources, we optimized experimental conditions and data analysis pipelines to achieve better consistency between results from high-throughput and individual validations. Furthermore, we evaluated the performance of scCRISPR immune screens in determining underlying mechanisms of tumor intrinsic immune regulation. Our results showed that scCRISPR platforms can simultaneously characterize gene expression profiles and perturbation effects present in individual cells in different immune screen conditions. Results from scCRISPR immune screens also predict transcriptional phenotype associated with clinical responses to cancer immunotherapy. More importantly, scCRISPR screen platforms reveal the interactive relationship between targeting tumor intrinsic factors and T cell-mediated antitumor immune response which cannot be easily assessed by bulk RNA-seq. Collectively, scCRISPR immune screens provide scalable and reliable platforms to elucidate molecular determinants of tumor immune resistance.
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- 2022
139. Enhancer Reprogramming in Melanoma Immune Checkpoint Therapy Resistance
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Mayinuer Maitituoheti, Alvin Shi, Ming Tang, Li-Lun Ho, Christopher Terranova, Kyriaki Galani, Emily Z. Keung, Caitlin A. Creasy, Manrong Wu, Jiajia Chen, Nana Chen, Anand K. Singh, Apoorvi Chaudhri, Nazanin E. Anvar, Giuseppe Tarantino, Jiekun Yang, Sharmistha Sarkar, Shan Jiang, Jared Malke, Lauren Haydu, Elizabeth Burton, Michael A. Davies, Jeffrey E. Gershenwald, Patrick Hwu, Alexander Lazar, Jaime H. Cheah, Christian K. Soule, Stuart S. Levine, Chantale Bernatchez, Srinivas V. Saladi, David Liu, Jennifer Wargo, Genevieve M. Boland, Manolis Kellis, and Kunal Rai
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Immune checkpoint blockade (ICB) therapy has improved long-term survival for patients with advanced melanoma. However, there is critical need to identify potential biomarkers of response and actionable strategies to improve response rates. Through generation and analysis of 148 chromatin modification maps for 36 melanoma samples from patients treated with anti-PD- 1, we identified significant enrichment of active enhancer states in non-responders at baseline. Analysis of an independent cohort of 20 samples identified a set of 437 enhancers that predicted response to anti-PD-1 therapy (Area Under the Curve of 0.8417). The activated non-responder enhancers marked a group of key regulators of several pathways in melanoma cells (including c- MET, TGFβ, EMT and AKT) that are known to mediate resistance to ICB therapy and several checkpoint receptors in T cells. Epigenetic editing experiments implicated involvement of c-MET enhancers in the modulation of immune response. Finally, inhibition of enhancers and repression of these pathways using bromodomain inhibitors along with anti-PD-1 therapy significantly decreased melanoma tumor burden and increased T-cell infiltration. Together, these findings identify a potential enhancer-based biomarker of resistance to anti-PD-1 and suggest enhancer blockade in combination with ICB as a potential strategy to improve responses.
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- 2022
140. Abstract 6425: Functional roles of enhancers in immune microenvironment & immunotherapy response
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Kunal Rai, Mayinuer Maitituoheti, Alvin Shi, Ming Tang, Li-Lun Ho, Firas Youssef Kreidieh, Christopher Terranova, Kyriakitsa Galani, Emily Z. Keung, Caitlin A. Creasy, Manrong Wu, Jiajia Chen, Nana Chen, Anand K. Singh, Apoorvi Chaudhri, Nazanin E. Anvar, Giuseppe Tarrantino, Jiekun Yang, Sharmistha Sarkar, Shan Jiang, Jared Malke, Lauren Haydu, Elizabeth Burton, Michael A. Davies, Jeffrey E. Gershenwald, Patrick Hwu, Alexander Lazar, Jaime H. Cheah, Christian K. Soule, Stuart S. Levine, Chantale Bernatchez, Srinivas V. Saladi, David Liu, Hussein Tawbi, Jennifer Wargo, Genevieve M. Boland, and Manolis Kellis
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Cancer Research ,Oncology - Abstract
Immune checkpoint blockade (ICB) therapy has improved long-term survival for patients with advanced melanoma. However, there is critical need to identify potential biomarkers of response and actionable strategies to improve response rates. Through generation and analysis of over 200 chromatin modification maps for ICB-treated melanoma patient samples, melanoma cells and T cells, we identified significant enrichment of active enhancer states in non-responders at baseline. Enhancer mapping by bulk ChIP-Seq or single cell ATAC-Seq methods in two independent cohorts of ICB-treated melanoma samples identified an enhancer signature that predicted response to anti-PD-1 therapy. The activated non-responder enhancers marked a group of key regulators of several pathways in melanoma cells (including c-MET, TGFβ, EMT and AKT) that are known to mediate resistance to ICB therapy. In addition, several checkpoint receptors were alternatively activated by aberrant enhancers in T cells. Unbiased CRISPRi screening in melanoma cells and T cells identified novel functional enhancers, such as one upstream of c-MET, that mediate ICB response or T cell mediated killing. Finally, inhibition of enhancers and repression of these pathways using bromodomain inhibitors along with anti-PD-1 therapy significantly decreased melanoma tumor burden and increased T-cell infiltration. Epigenomic experiments identified a signature of 107 genes that could be used as pharmacodynamic marker for BET inhibitor response. Together, these findings identify enhancer upregulation as a key mechanism of adaptive resistance to ICB response, a potential enhancer-based biomarker of resistance to anti-PD-1 and enhancer blockade in combination with ICB as a potential strategy to improve responses. Citation Format: Kunal Rai, Mayinuer Maitituoheti, Alvin Shi, Ming Tang, Li-Lun Ho, Firas Youssef Kreidieh, Christopher Terranova, Kyriakitsa Galani, Emily Z. Keung, Caitlin A. Creasy, Manrong Wu, Jiajia Chen, Nana Chen, Anand K. Singh, Apoorvi Chaudhri, Nazanin E. Anvar, Giuseppe Tarrantino, Jiekun Yang, Sharmistha Sarkar, Shan Jiang, Jared Malke, Lauren Haydu, Elizabeth Burton, Michael A. Davies, Jeffrey E. Gershenwald, Patrick Hwu, Alexander Lazar, Jaime H. Cheah, Christian K. Soule, Stuart S. Levine, Chantale Bernatchez, Srinivas V. Saladi, David Liu, Hussein Tawbi, Jennifer Wargo, Genevieve M. Boland, Manolis Kellis. Functional roles of enhancers in immune microenvironment & immunotherapy response. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6425.
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- 2023
141. Blueprint for the discovery of biomarkers of toxicity and efficacy for CAR T cells and T-cell engagers
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Stephen R. Spellman, Leslie S. Kean, Chantale Bernatchez, Miguel-Angel Perales, Verena Staedtke, Amit Agarwal, Sophie Paczesny, Marcelo C. Pasquini, Steven Z. Pavletic, and Juliane Gust
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business.industry ,T-Lymphocytes ,T cell ,Receptors, Antigen, T-Cell ,Hematology ,Immunotherapy, Adoptive ,medicine.anatomical_structure ,Toxicity ,Commentary ,Cancer research ,Medicine ,Car t cells ,business ,Biomarkers - Published
- 2021
142. 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
143. T-cell potential for CD19-expressing malignancies revealed by multi-dimensional single-cell profiling
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Ali Rezvan, Gabrielle Romain, Mohsen Fathi, Darren Heeke, Melisa Martinez-Paniagua, Xingyue An, Irfan N Bandey, Arash Saeedi, Fatemeh Sadeghi, Kristen Fousek, Nahum Puebla-Osorio, Laurence J.N. Cooper, Chantale Bernatchez, Harjeet Singh, Nabil Ahmed, Mike Mattie, Adrian Bot, Sattva Neelapu, and Navin Varadarajan
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Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CARs) for B-cell malignancies serves as a model for identifying subsets with superior clinical activity. We profiled the infusion products (IP) of 16 patients with large B-cell lymphoma (LBCL) using an integrated suite of single-cell assays to reveal the therapeutic potential of CD19-specific CAR+ T cells. Timelapse imaging microscopy in nanowell grids (TIMING) profiling revealed that T cells from responders showed migration (persistent motion for at least one body length), and migration was associated with serial killing capacity. In addition, confocal microscopy revealed that migration is linearly correlated with both mitochondrial volume and lysosomal volume; and scRNA-seq demonstrated that T cells from responders were enriched in pathways related to T-cell killing, migration and actin cytoskeleton, and TCR clustering. A marker-free sorting strategy enriched T cells with migratory capacity and validated serial killing, bioenergetics, and in vivo efficacy. In aggregate, we demonstrate that migration is a cell-intrinsic biomarker independent of CAR design or biomanufacturing, desired in the bioactivity of CAR+ T cells associated with clinical antitumor efficacy.
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- 2022
144. CRISPR-mediated TGFBR2 knockout renders human ovarian cancer tumor-infiltrating lymphocytes resistant to TGF-β signaling
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Samantha M Fix, Marie-Andrée Forget, Donastas Sakellariou-Thompson, Yunfei Wang, Tamara M Griffiths, Minjung Lee, Cara L Haymaker, Ana Lucía Dominguez, Rafet Basar, Christopher Reyes, Sanjay Kumar, Larissa A Meyer, Patrick Hwu, Chantale Bernatchez, and Amir A Jazaeri
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Pharmacology ,Ovarian Neoplasms ,Cancer Research ,Immunology ,Receptor, Transforming Growth Factor-beta Type II ,Carcinoma, Ovarian Epithelial ,Immunotherapy, Adoptive ,Lymphocytes, Tumor-Infiltrating ,Oncology ,Transforming Growth Factor beta ,Tumor Microenvironment ,Molecular Medicine ,Immunology and Allergy ,Humans ,Female - Abstract
BackgroundThe correlation between elevated T-cell infiltration and improved survival of ovarian cancer (OvCa) patients suggests that endogenous tumor-infiltrating lymphocytes (TIL) possess some degree of antitumor activity that can be harnessed for OvCa immunotherapy. We previously optimized a protocol for ex vivo OvCa TIL expansion for adoptive cell therapy, which is now being tested in a clinical trial at our institution (NCT03610490). Building on this success, we embarked on genetic modification of OvCa TIL to overcome key immunosuppressive factors present in the tumor microenvironment. Here, we present the preclinical optimization of CRISPR/Cas9-mediated knockout of the TGF-β receptor 2 (TGFBR2) in patient-derived OvCa TIL.MethodsOvCa TILs were generated from four patients’ tumor samples obtained at surgical resection and subjected to CRISPR/Cas9-mediated knockout of TGFBR2 before undergoing a rapid expansion protocol. TGFBR2-directed gRNAs were comprehensively evaluated for their TGFBR2 knockout efficiency and off-target activity. Furthermore, the impact of TGFBR2 knockout on TIL expansion, function, and downstream signaling was assayed.ResultsTGFBR2 knockout efficiencies ranging from 59±6% to 100%±0% were achieved using 5 gRNAs tested in four independent OvCa TIL samples. TGFBR2 knockout TIL were resistant to immunosuppressive TGF-β signaling as evidenced by a lack of SMAD phosphorylation, a lack of global transcriptional changes in response to TGF-β stimulation, equally strong secretion of proinflammatory cytokines in the presence and absence of TGF-β, and improved cytotoxicity in the presence of TGF-β. CRISPR-modification itself did not alter the ex vivo expansion efficiency, immunophenotype, nor the TCR clonal diversity of OvCa TIL. Importantly for clinical translation, comprehensive analysis of CRISPR off-target effects revealed no evidence of off-target activity for our top two TGFBR2-targeting gRNAs.ConclusionsCRISPR/Cas9-mediated gene knockout is feasible and efficient in patient-derived OvCa TIL using clinically-scalable methods. We achieved efficient and specific TGFBR2 knockout, yielding an expanded OvCa TIL product that was resistant to the immunosuppressive effects of TGF-β. This study lays the groundwork for clinical translation of CRISPR-modified TIL, providing opportunities for engineering more potent TIL therapies not only for OvCa treatment, but for the treatment of other solid cancers as well.
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- 2022
145. Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial
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Neeta Somaiah, Anthony P Conley, Edwin Roger Parra, Heather Lin, Behrang Amini, Luisa Solis Soto, Ruth Salazar, Carmelia Barreto, Honglei Chen, Swati Gite, Cara Haymaker, Elise F Nassif, Chantale Bernatchez, Akash Mitra, John Andrew Livingston, Vinod Ravi, Dejka M Araujo, Robert Benjamin, Shreyaskumar Patel, Maria A Zarzour, Sharjeel Sabir, Alexander J Lazar, Wei-Lien Wang, Najat C Daw, Xiao Zhou, Christina L Roland, Zachary A Cooper, Jaime Rodriguez-Canales, Andrew Futreal, Jean-Charles Soria, Ignacio I Wistuba, and Patrick Hwu
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Osteosarcoma ,Sarcoma, Alveolar Soft Part ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Microenvironment ,Antibodies, Monoclonal ,Humans ,Bone Neoplasms ,Soft Tissue Neoplasms ,Pneumonia ,Antibodies, Monoclonal, Humanized ,Colitis - Abstract
Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes.In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed.Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis.The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials.AstraZeneca.
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- 2022
146. 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
147. 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
148. 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
149. Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity
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Cara Haymaker, Jason Roszik, Jie Qing Chen, Jahan Khalili, Zhe Wang, Nikunj Satani, Rina M. Mbofung, Laurence J.N. Cooper, Marie-Andree Forget, Willem W. Overwijk, Chunyu Xu, Leila Williams, Weiyi Peng, Chengwen Liu, Deborah A. Silverman, Simone Punt, Sourindra Maiti, Florian L. Muller, Elien M Doorduijn, Chantale Bernatchez, Trang N. Tieu, Ana Lucia Dominguez, Soraya Zorro Manrique, Patrick Hwu, Shruti Malu, Emily Ashkin, Jodi A. McKenzie, Rodabe N. Amaria, and Timothy P. Heffernan
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Cancer Research ,High-throughput screen ,medicine.medical_treatment ,Immunology ,Apoptosis ,Mice ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Aurora kinase ,In vivo ,Tumor Cells, Cultured ,Tumor Microenvironment ,medicine ,Animals ,Aurora Kinase B ,Humans ,Immunology and Allergy ,Cytotoxicity ,Melanoma ,Aurora Kinase A ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Tumor microenvironment ,Chemistry ,T-cell cytotoxicity ,Immunotherapy ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Survival Rate ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Original Article ,Female ,T cell mediated cytotoxicity ,Immune checkpoint blockade ,T-Lymphocytes, Cytotoxic - Abstract
Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention. Electronic supplementary material The online version of this article (10.1007/s00262-020-02748-9) contains supplementary material, which is available to authorized users.
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- 2020
150. The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity
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Patricia Ho, Johannes C. Melms, Meri Rogava, Chris J. Frangieh, Shivem B. Shah, Zachary Walsh, Oleksandr Kyrysyuk, Amit Dipak Amin, Lindsay Caprio, Benjamin T. Fullerton, Rajesh Soni, Casey R. Ager, Jana Biermann, Yiping Wang, Michael Mu, Hijab Fatima, Emily K. Moore, Neil Vasan, Samuel F. Bakhoum, Steven L. Reiner, Chantale Bernatchez, Emily M. Mace, Kai W. Wucherpfennig, Dirk Schadendorf, Gary K. Schwartz, and Benjamin Izar
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The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 coimmunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary costimulatory signals required for response to PD-1 blockade (e.g. CD28), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2-expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.
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- 2022
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