100 results on '"Theresa LaVallee"'
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2. Society for Immunotherapy of Cancer (SITC) checkpoint inhibitor resistance definitions: efforts to harmonize terminology and accelerate immuno-oncology drug development
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Jeffrey Sosman, Elad Sharon, Theresa LaVallee, Hussein A Tawbi, Ryan J Sullivan, Harriet M Kluger, Naiyer A Rizvi, and David Feltquate
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The need for solid clinical definitions of resistance to programmed death 1 or its ligand (PD-(L)1) inhibitors for clinical trial design was identified as a priority by the Society for Immunotherapy of Cancer (SITC). Broad consensus efforts have provided definitions for primary and secondary resistance and resistance after stopping therapy for both single-agent PD-(L)1 inhibitors and associated combinations. Validation of SITC’s definitions is critical and requires field-wide data sharing and collaboration. Here, in this commentary, we detail current utility and incorporation of SITC’s definitions and discuss the next steps both the society and the field must take to further advance immuno-oncology drug development.
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- 2023
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3. The 'Great Debate' at Immunotherapy Bridge 2021, December 1st–2nd, 2021
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Paolo A. Ascierto, Lisa H. Butterfield, Olivera J. Finn, Andrew Futreal, Omid Hamid, Theresa LaVallee, Michael A. Postow, Igor Puzanov, Jeffrey Sosman, Bernard A. Fox, and Patrick Hwu
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Immunotherapy ,Cancer vaccine ,Checkpoint inhibitors ,Nivolumab ,Pembrolizumab ,Overall survival ,Medicine - Abstract
Abstract As part of the 2021 Immunotherapy Bridge virtual congress (December 1–2, Naples, Italy), the Great Debate sessions featured experts who were assigned counter opposing views on four important questions in immunotherapy today. The first topic was whether oncolytic viruses or other specific immunomodulators were the more promising approach for intralesional therapy. The second was whether early surrogate endpoints, such as response rate or progression-free survival, correlate with long-term overall survival was considered. Thirdly, whether vaccines can transform cold into hot tumors was discussed and, finally, broad versus deep analytic profiling approaches to gain insights into immune-oncology development were compared. As with previous Bridge congresses, presenters were invited by the meeting Chairs and positions taken during the debates may not have reflected their respective personal view. In addition, the views summarised in this article are based on available evidence but may reflect personal interpretation of these data, clinical experience and subjective opinion of the speaker.
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- 2022
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4. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors
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Harriet Kluger, Omid Hamid, Roberta Zappasodi, Michael Hurwitz, Hussein Tawbi, Elad Sharon, Theresa LaVallee, Rebecca A Moss, Justin F Gainor, J Carl Barrett, and Ryan J Sullivan
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Immunotherapy is the standard of care for several cancers and the field continues to advance at a rapid pace, with novel combinations leading to indications in an increasing number of disease settings. Durable responses and long-term survival with immunotherapy have been demonstrated in some patients, though lack of initial benefit and recurrence after extended disease control remain major hurdles for the field. Many new combination regimens are in development for patients whose disease progressed on initial immunotherapy. To guide clinical trial design and support analyses of emerging molecular and cellular data surrounding mechanisms of resistance, the Society for Immunotherapy of Cancer (SITC) previously generated consensus clinical definitions for resistance to single-agent anti-PD-1 immune checkpoint inhibitors (ICIs) in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. An unmet need still exists, however, for definitions of resistance to ICI-based combinations, which represent an expanding frontier in the immunotherapy treatment landscape. In 2021, SITC convened a workshop including stakeholders from academia, industry, and government to develop consensus definitions for resistance to ICI-based combination regimens for improved outcome assessment, trial design and drug development. This manuscript reports the minimum drug exposure requirements and time frame for progression that define resistance in both the metastatic setting and the perioperative setting, as well as key caveats and areas for future research with ICI/ICI combinations. Definitions for resistance to ICIs in combination with chemotherapy and targeted therapy will be published in companion volumes to this paper.
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- 2023
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5. Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses
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Antoni Ribas, Paul Chapman, Katherine S Panageas, Michael Postow, Joyson Karakunnel, Hussein Tawbi, Christine Spencer, Katy Tsai, Ramy Ibrahim, Jedd Wolchok, Theresa LaVallee, Travis J Hollmann, Alexander Shoushtari, Daniel K Wells, Margaret Callahan, Samantha Bucktrout, Claire F Friedman, Christopher R Cabanski, Pier Gherardini, and Richard O Chen
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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6. 305 Technical considerations for normalizing digital spatial profiling data with multiple within-patient samples
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Sarah Warren, Jason Reeves, Christine Spencer, Travis Hollman, Claire Friedman, Theresa LaVallee, Tim Howes, and Danny Wells
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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7. Altered expression of insulin receptor isoforms in breast cancer.
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Jiaqi Huang, Chris Morehouse, Katie Streicher, Brandon W Higgs, Jin Gao, Meggan Czapiga, Anmarie Boutrin, Wei Zhu, Philip Brohawn, Yong Chang, Jaye Viner, Theresa LaVallee, Laura Richman, Bahija Jallal, and Yihong Yao
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Medicine ,Science - Abstract
PURPOSE: Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) contributes to tumorigenesis and intrinsic resistance to anti-IGF1R therapy. In the present study, we (a) developed quantitative TaqMan real time-PCR-based assays (qRT-PCR) to measure human insulin receptor isoforms with high specificity, (b) evaluated isoform expression levels in molecularly-defined breast cancer subtypes, and (c) identified the IR-A:IR-B mRNA ratio as a potential biomarker guiding patient stratification for anti-IGF therapies. EXPERIMENTAL DESIGN: mRNA expression levels of IR-A and IR-B were measured in 42 primary breast cancers and 19 matched adjacent normal tissues with TaqMan qRT-PCR assays. The results were further confirmed in 165 breast cancers. The tumor samples were profiled using whole genome microarrays and subsequently subtyped using the PAM50 breast cancer gene signature. The relationship between the IR-A:IR-B ratio and cancer subtype, as well as markers of proliferation were characterized. RESULTS: The mRNA expression levels of IR-A in the breast tumors were similar to those observed in the adjacent normal tissues, while the mRNA levels of IR-B were significantly decreased in tumors. The IR-A:IR-B ratio was significantly higher in luminal B breast cancer than in luminal A. Strong concordance between the IR-A:IR-B ratio and the composite Oncotype DX proliferation score was observed for stratifying the latter two breast cancer subtypes. CONCLUSIONS: The reduction in IR-B expression is the key to the altered IR-A:IR-B ratio observed in breast cancer. The IR-A:IR-B ratio may have biomarker utility in guiding a patient stratification strategy for an anti-IGF therapeutic.
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- 2011
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8. Data from Phase I Dose-Escalation Study of MEDI-573, a Bispecific, Antiligand Monoclonal Antibody against IGFI and IGFII, in Patients with Advanced Solid Tumors
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Patricia LoRusso, Jennifer McDevitt, Jaye Viner, Jaiqi Huang, Patricia Burke, Xiang-Qing Yu, Li Shi, Theresa LaVallee, Donald Northfelt, Jonathan Rosenberg, Elizabeth R. Plimack, Michael Menefee, and Paul Haluska
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Purpose: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists.Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity.Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response.Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. Clin Cancer Res; 20(18); 4747–57. ©2014 AACR.
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- 2023
9. Supplemental Figure 2 from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Jennifer R. Grandis, Julie E. Bauman, Michelle A. Ozbun, Daniel E. Johnson, Theresa LaVallee, Umamaheswar Duvvuri, Carolyn Kemp, Nevan J. Krogan, Margaret Soucheray, Sourav Bandyopadhyay, Max V. Ranall, Rachel A. O'Keefe, Yan Zeng, Hua Li, Neil E. Bhola, Stefan Hartmann, and Toni M. Brand
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Pan-phospho-RTK profiling identifies HER3 to be hyper-phosphorylated after BYL719 treatment in HPV(+) cell lines
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- 2023
10. Supplemental Figure 1 from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Jennifer R. Grandis, Julie E. Bauman, Michelle A. Ozbun, Daniel E. Johnson, Theresa LaVallee, Umamaheswar Duvvuri, Carolyn Kemp, Nevan J. Krogan, Margaret Soucheray, Sourav Bandyopadhyay, Max V. Ranall, Rachel A. O'Keefe, Yan Zeng, Hua Li, Neil E. Bhola, Stefan Hartmann, and Toni M. Brand
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HPV(+) cell lines are less responsive to BKM120 and BEZ235 than HPV(-) cell lines
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- 2023
11. Data from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Jennifer R. Grandis, Julie E. Bauman, Michelle A. Ozbun, Daniel E. Johnson, Theresa LaVallee, Umamaheswar Duvvuri, Carolyn Kemp, Nevan J. Krogan, Margaret Soucheray, Sourav Bandyopadhyay, Max V. Ranall, Rachel A. O'Keefe, Yan Zeng, Hua Li, Neil E. Bhola, Stefan Hartmann, and Toni M. Brand
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Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors.Significance: These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. Cancer Res; 78(9); 2383–95. ©2018 AACR.
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- 2023
12. Data Supplement from Phase I Dose-Escalation Study of MEDI-573, a Bispecific, Antiligand Monoclonal Antibody against IGFI and IGFII, in Patients with Advanced Solid Tumors
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Patricia LoRusso, Jennifer McDevitt, Jaye Viner, Jaiqi Huang, Patricia Burke, Xiang-Qing Yu, Li Shi, Theresa LaVallee, Donald Northfelt, Jonathan Rosenberg, Elizabeth R. Plimack, Michael Menefee, and Paul Haluska
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Figure S1. Top: mRNA differential expression of individual proliferation genes (AURKA, CCNB1, MKI67, and MYBL2) and cancer invasion genes (CTSL2 and MMP11) and the bladder cancer marker, UPK3A, in biopsy samples (from patients with bladder cancer at pretreatment and after treatment at 5 mg/kg and 15 mg/kg. Bottom: Composite differential expression score from pretreatment and post-treatment tissues of proliferation, invasion, and bladder cancer markers in cohorts 5 mg/kg and 15 mg/kg.
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- 2023
13. Supplemental Figure 3 from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Jennifer R. Grandis, Julie E. Bauman, Michelle A. Ozbun, Daniel E. Johnson, Theresa LaVallee, Umamaheswar Duvvuri, Carolyn Kemp, Nevan J. Krogan, Margaret Soucheray, Sourav Bandyopadhyay, Max V. Ranall, Rachel A. O'Keefe, Yan Zeng, Hua Li, Neil E. Bhola, Stefan Hartmann, and Toni M. Brand
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Blockade of the PI3K pathway with BKM120 or BEZ235 increases HER3/AKT signaling
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- 2023
14. Supplemental Figure Legends from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Jennifer R. Grandis, Julie E. Bauman, Michelle A. Ozbun, Daniel E. Johnson, Theresa LaVallee, Umamaheswar Duvvuri, Carolyn Kemp, Nevan J. Krogan, Margaret Soucheray, Sourav Bandyopadhyay, Max V. Ranall, Rachel A. O'Keefe, Yan Zeng, Hua Li, Neil E. Bhola, Stefan Hartmann, and Toni M. Brand
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Legend for supplemental figures
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- 2023
15. Data from Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients
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Julie E. Bauman, Jennifer R. Grandis, Theresa LaVallee, Thomas Hawthorne, Richard Gedrich, Ahmed Chenna, Veronique M. Neumeister, Diego Alvarado, Seungwon Kim, Jonathan George, and Umamaheswar Duvvuri
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Purpose:ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A “window-of-opportunity” study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC.Patients and Methods:Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed.Results:pErbB3 was detectable in all tumors prior to treatment and decreased for 10 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 27.7%–84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment–related toxicity was grade 1–2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus–negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment.Conclusions:This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.
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- 2023
16. Supplemental Table I from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Jennifer R. Grandis, Julie E. Bauman, Michelle A. Ozbun, Daniel E. Johnson, Theresa LaVallee, Umamaheswar Duvvuri, Carolyn Kemp, Nevan J. Krogan, Margaret Soucheray, Sourav Bandyopadhyay, Max V. Ranall, Rachel A. O'Keefe, Yan Zeng, Hua Li, Neil E. Bhola, Stefan Hartmann, and Toni M. Brand
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Clinical characteristics of patients prior to surgery and PDX establishment
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- 2023
17. Supplemental Figure 4 from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Jennifer R. Grandis, Julie E. Bauman, Michelle A. Ozbun, Daniel E. Johnson, Theresa LaVallee, Umamaheswar Duvvuri, Carolyn Kemp, Nevan J. Krogan, Margaret Soucheray, Sourav Bandyopadhyay, Max V. Ranall, Rachel A. O'Keefe, Yan Zeng, Hua Li, Neil E. Bhola, Stefan Hartmann, and Toni M. Brand
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HER3 blockade enhances the sensitivity of HPV(+) cell lines to BKM120
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- 2023
18. Hallmarks of Resistance to Immune-Checkpoint Inhibitors
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Maria Karasarides, Alexandria P. Cogdill, Paul B. Robbins, Michaela Bowden, Elizabeth M. Burton, Lisa H. Butterfield, Alessandra Cesano, Christian Hammer, Cara L. Haymaker, Christine E. Horak, Heather M. McGee, Anne Monette, Nils-Petter Rudqvist, Christine N. Spencer, Randy F. Sweis, Benjamin G. Vincent, Erik Wennerberg, Jianda Yuan, Roberta Zappasodi, Vanessa M. Hubbard Lucey, Daniel K. Wells, and Theresa LaVallee
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Cancer Research ,Immunological ,Good Health and Well Being ,Antineoplastic Agents, Immunological ,Neoplasms ,Oncology and Carcinogenesis ,Immunology ,Humans ,Antineoplastic Agents ,Pharmacology and Pharmaceutical Sciences ,Immune Checkpoint Inhibitors ,Cancer - Abstract
Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes.
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- 2022
19. 587 AMADEUS trial: tumor agnostic pre- and on-treatment biomarkers of response to nivolumab plus ipilimumab correlate with on-treatment tumoral T cell infiltration
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Farah Alayli, Kwame Okrah, Apostolia Tsimberidou, Alexandra Drakaki, Danny Khalil, Saad Khan, Stephen Hodi, David Oh, Meelad Amouzgar, Shikha Guatam, Robin Kageyama, Shannon Pfeiffer, Stefanie Meier, Christopher Cabanski, Diane Da Silva, Dinesh Kumar, Sandra Santulli-Marotto, Michael Tetzlaff, Wai Chin Foo, Travis Hollman, Yanyun Li, Mathew Adamow, Philip Wong, Marko Spasic, Richard Chen, Samantha Bucktrout, Justin Fairchild, Lisa Butterfield, Theresa LaVallee, Lacey Padron, Lisa Salvador, Jill O’Donnell-Tormey, Ute Dugan, and Padmanee Sharma
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- 2022
20. 555 Clinical and pharmacodynamic biomarker results from PORTER, a multi-cohort phase 1 platform trial of combination immunotherapy for metastatic castration-resistant prostate cancer patients
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Matthew Galsky, Karen Autio, Kristopher Wentzel, Julie Graff, Terence Friedlander, Julie Densmore, Christopher Cabanski, Kristin Shotts, Tim Howes, Jia Yu, Elaine Eisenbeisz, Marko Spasic, Stephen Maddock, Diane DaSilva, Dinesh Kumar, Jonni Moore, Richard Schretzenmair, Jennifer Lata, Arron Xu, Emma Reuschel, Snehal Wani, Matthew Morrow, Jeffrey Skolnik, Sandra Santulli-Marotto, Lacey Padron, Lisa Butterfield, Theresa LaVallee, Samantha Bucktrout, Michael Yellin, Tibor Keler, Lisa Salvador, Jill O'Donnell-Tormey, Vanessa Lucey, Justin Fairchild, Ute Dugan, Nina Bhardwaj, Sumit Subudhi, and Lawrence Fong
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- 2022
21. 607 MCGRAW trial: evaluation of the safety and efficacy of an oral microbiome intervention (SER-401) in combination with nivolumab in first line metastatic melanoma patients
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Isabella Glitza Oliva, Omid Hamid, Patrick Ott, Genevieve Boland, Ryan Sullivan, Kenneth Grossmann, Christopher Desjardins, Nathan Hicks, Brian Weiner, Farah Alayli, Christine Spencer, Shikha Guatam, Christopher Loo, Benjamin Kamphaus, Julie Densmore, Christopher Cabanski, Diane Da Silva, Jennifer Wargo, Justin Fairchild, Marko Spasic, John Aunins, Kelly Brady, Elizabeth Burton, Jennifer Wortman, Theresa LaVallee, Mathew Henn, and Hussein Tawbi
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- 2022
22. 656 Exploratory platform trial to evaluate immunotherapy combinations with chemotherapy for the treatment of patients with previously untreated metastatic pancreatic adenocarcinoma (REVOLUTION)
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Jaclyn Lyman, Eileen O’Reilly, Zev Wainberg, George Fisher, Robert Wolff, Andrew Ko, Mark O’Hara, Harshabad Singh, Ravi Amaravadi, Alec Kimmelman, Eric Collison, Danny Khalil, Rosemarie Schmidberger, Christopher Cabanski, Stephen Maddock, Marko Spasic, Deena Maurer, Diane Da Silva, Christopher Perry, Jia Xin Yu, Lacey Padrón, Samantha Bucktrout, Lisa Butterfield, Ramy Ibrahim, Justin Fairchild, Theresa LaVallee, Thomas Lillie, William Hoos, Silvia Boffo, Ute Dugan, Jill O’Donnell-Tormey, and Robert Vonderheide
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- 2022
23. 559 Biomarker correlates of clinical response with FLT3L/nivo backbone treatment in the multi-cohort phase 1 PORTER platform trial in metastatic castration-resistant prostate cancer patients
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Kristin Shotts, Timothy Howes, Jia Yu, Julie Densmore, Diane Da Silva, Dinesh Kumar, Sandra Santulli-Marotto, Christopher Cabanski, Elaine Eisenbeisz, Geoffrey Ivison, Aaron Mayer, Jonni Moore, Derek Jones, Kimberly Kraynyak, Alex Dolgoter, Richard Chen, Lisa Butterfield, Theresa LaVallee, Samantha Bucktrout, Lacey Padron, Ute Dugan, Michael Yellin, Tibor Keler, Jill O'Donnell-Tormey, Justin Fairchild, Lisa Salvador, Kristopher Wentzel, Lawrence Fong, Sumit Subudhi, Nina Bhardwaj, Karen Autio, and Matthew Galsky
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- 2022
24. Correction: Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Toni M. Brand, Stefan Hartmann, Neil E. Bhola, Hua Li, Yan Zeng, Rachel A. O'Keefe, Max V. Ranall, Sourav Bandyopadhyay, Margaret Soucheray, Nevan J. Krogan, Carolyn Kemp, Umamaheswar Duvvuri, Theresa LaVallee, Daniel E. Johnson, Michelle A. Ozbun, Julie E. Bauman, and Jennifer R. Grandis
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Cancer Research ,Oncology - Published
- 2022
25. Editor's Note: Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Toni M. Brand, Stefan Hartmann, Neil E. Bhola, Hua Li, Yan Zeng, Rachel A. O'Keefe, Max V. Ranall, Sourav Bandyopadhyay, Margaret Soucheray, Nevan J. Krogan, Carolyn Kemp, Umamaheswar Duvvuri, Theresa LaVallee, Daniel E. Johnson, Michelle A. Ozbun, Julie E. Bauman, and Jennifer R. Grandis
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Cancer Research ,Oncology - Published
- 2022
26. HER3 targeting potentiates growth suppressive effects of the PI3K inhibitor BYL719 in pre-clinical models of head and neck squamous cell carcinoma
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Theresa LaVallee, Neal R. Godse, Sucheta Kulkarni, Jennifer R. Grandis, Kara S. Meister, Diego Alvarado, Matthew L. Hedberg, Nayel I. Khan, Seungwon Kim, Carolyn Kemp, and Umamaheswar Duvvuri
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0301 basic medicine ,Receptor, ErbB-3 ,lcsh:Medicine ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,ErbB-3 ,Molecular Targeted Therapy ,Head and neck cancer ,Receptor ,lcsh:Science ,Cancer genetics ,Cancer ,Phosphoinositide-3 Kinase Inhibitors ,Tumor ,Multidisciplinary ,Chemistry ,Drug Synergism ,Up-Regulation ,3. Good health ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Signal transduction ,Signal Transduction ,Article ,Cell Line ,03 medical and health sciences ,Rare Diseases ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Dental/Oral and Craniofacial Disease ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Squamous Cell Carcinoma of Head and Neck ,lcsh:R ,medicine.disease ,Xenograft Model Antitumor Assays ,Head and neck squamous-cell carcinoma ,body regions ,Thiazoles ,030104 developmental biology ,Cell culture ,Cancer research ,lcsh:Q ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery - Abstract
BYL719 is a PI3K inhibitor that has demonstrated efficacy in the treatment of head and neck squamous cell carcinoma. BYL719 exerts its therapeutic effect by suppressing AKT and other proliferative signaling mechanisms. Despite PI3K inhibition and AKT suppression, residual activity of protein S6, a core marker of proliferative activation, has been observed. HER3, either via dimerization or activation by its ligand neurgeulin (NRG), is known to activate PI3K. Thus, we hypothesized that co-targeting HER3 and PI3K would lead to greater suppression of the PI3K-AKT signaling pathway and greater tumor suppression than with BYL719 alone. We investigated biochemical expression and activation of the HER3-PI3K-AKT-S6 pathway in HNSCC cell lines and patient-derived xenografts (PDXs). Antitumor effects of HER3 and PI3K inhibitors alone and in combination were evaluated in cell culture and murine models. Treatment of HNSCC cell lines with BYL719 significantly reduced AKT activation and suppressed tumor growth. However, S6 was persistently activated despite suppression of AKT. Combination treatment with KTN3379, a monoclonal antibody targeted against HER3, and BYL719 led to enhanced suppression of in vitro and in vivo cancer growth and durable suppression of AKT and S6. Therefore, inhibition of HER3 with KTN3379 enhanced the effects of PI3K inhibition in pre-clinical HNSCC models. These data support co-targeting HER3 and PI3K for the treatment of HSNCC.
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- 2019
27. Abstract 66: A multi-institution examination of concordance in spatial transcriptomics using the GeoMx Cancer Transcriptome Atlas
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Tyler Hether, Tim Howes, David Scoville, Charlie Glaser, Yanyun Li, Rami Vanguri, Neeman Mohibullah, Wan-Jung Chang, Todd Yoder, Minnal Gupta, Kathy Ton, Yan Liang, Ying Huang, Zach Herbert, Jason Reeves, Elizabeth Mittendorf, Simon Lacey, Travis Hollmann, Sarah Warren, and Theresa LaVallee
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Cancer Research ,Oncology - Abstract
Multiplexed spatial profiling can enable biological insights by characterizing gene expression within discrete physical locations of a tissue. However, these advanced techniques can be confounded by variability of sample collection, storage, or profiling protocols, making it difficult to accurately compare data generated by different laboratories. Further, as more spatial profiling datasets become publicly available, having methods to enable meta-analysis of samples collected on different studies will maximize the learnings to support the advancement of treatments or identifying patient segments. To quantify the variability of spatial profiling data at different laboratories and to advance data normalization methodologies, 4 independent laboratories used the NanoString® GeoMx® Digital Spatial Profiling (DSP) to profile serial 5 µm sections of tissue and cell pellet arrays (CPAs). GeoMx DSP enables high throughput, spatially resolved analysis of gene or protein expression from fresh or archival human tissues. In this study, the GeoMx Cancer Transcriptome Atlas was used to profile >1800 genes simultaneously. We examined the concordance of GeoMx data generated in the different laboratories when controlling for methodical variation (e.g., reagents, tissue source) and experimentally varying region of interest (ROI) size, collection site, and sample preservation methods. Sections of tonsil, colon, and 2 CPAs were profiled separately at the 4 laboratories. Each analyzed fresh cut (FC) tissues and two sites examined sample stability by analyzing the impact of storing slides at -80°C for 1 month prior to spatial profiling. Concordance analysis was performed using the Horn-Morisita Index on raw data comparing paired and unpaired ROIs across each set of slides. In CPA samples where each pellet was a different tumor type (e.g., NSCLC, melanoma), we observed strong clustering by cell line. While data initially showed varying degrees of clustering by slide, factoring out this variable removed the association of slide, allowing integration of the data across profiling locations without affecting concordance within slides. In tonsil, ROIs with increasing area were profiled. Comparing expression between pairs of samples for a given area, concordance increased with ROI size (R = -0.40, p In this study, we quantify slide-specific variation observed in high-plex RNA profiling by the DSP platform and detail methods for accounting for this variation. We note that many downstream analyses (e.g., differential expression) already model slide effects during the analysis, but modeling it explicitly allows for direct comparison of concordance with other approaches (e.g., clustering, PCA). These methods support the use of multi-institution studies leveraging the GeoMx platform. Citation Format: Tyler Hether, Tim Howes, David Scoville, Charlie Glaser, Yanyun Li, Rami Vanguri, Neeman Mohibullah, Wan-Jung Chang, Todd Yoder, Minnal Gupta, Kathy Ton, Yan Liang, Ying Huang, Zach Herbert, Jason Reeves, Elizabeth Mittendorf, Simon Lacey, Travis Hollmann, Sarah Warren, Theresa LaVallee. A multi-institution examination of concordance in spatial transcriptomics using the GeoMx Cancer Transcriptome Atlas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 66.
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- 2022
28. Distinct biosignatures associate with survival after chemoimmunotherapy in a randomized, three-arm phase II study in patients with metastatic pancreatic cancer
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Lacey J. Padrón, Deena M. Maurer, Mark H. O'Hara, Eileen Mary O'Reilly, Robert A. Wolff, Zev A. Wainberg, Andrew H. Ko, George A. Fisher, Osama E. Rahma, Jaclyn P. Lyman, Christopher R. Cabanski, Jia Yu, Shannon M. Pfeiffer, Marko Spasic, Travis J Hollmann, Richard Chen, Jill O'Donnell-Tormey, Samantha Bucktrout, Theresa LaVallee, and Robert H. Vonderheide
- Subjects
Cancer Research ,Oncology - Abstract
4010 Background: Preclinical and small clinical studies of chemoimmunotherapy for metastatic pancreatic ductal adenocarcinoma (mPDAC) point to a yet unrealized potential of clinically significant immune activation. In our phase II study of the CD40 agonist antibody sotigalimab (sotiga) and/or nivolumab (nivo) with gemcitabine and nab-paclitaxel (chemo), we observed promising improvements in overall survival (OS) in 105 patients with newly diagnosed mPDAC (NCT03214250); the primary endpoint of 1-year OS rate was 57.7% (p = 0.006) in the nivo/chemo arm, 48.1% (p = 0.062) in the sotiga/chemo arm and 41.3% (p = 0.233) in the nivo/sotiga/chemo arm (O’Hara, ASCO 2021) as compared to a historical control of 35%. Here, we report results of multi-omic translational analyses designed to identify signatures predictive of OS benefit. Methods: Longitudinal blood and tumor tissue samples were collected for immune and tumor biomarker analysis. Tumor samples underwent RNA sequencing and multiplex immunofluorescence (mIF). Peripheral blood was analyzed by mass cytometry time of flight (CyTOF), high parameter flow cytometry, and proteomics. Machine learning (ML) algorithms were applied to the data to identify biosignatures related to OS in each arm. Results: Comprehensive multi-omic, multi-parameter immune and tumor biomarker analyses identified distinct pretreatment immune signatures predictive of longer OS specific to nivo/chemo or sotiga/chemo (Table, representative examples). Because patients in each arm received chemotherapy, these and other arm-unique biomarkers suggest a relationship to the immunotherapy rather than chemotherapy in this randomized study. There was evidence of immune exhaustion in the sotiga/nivo/chemo arm that may explain the lack of survival benefit. Conclusions: From in-depth translational and ML analyses of randomized phase II trial of first-line chemoimmunotherapy in mPDAC patients, we identified novel biomarkers that associated with OS distinctly in each arm. Clinical trials in first-line mPDAC exploiting these previously unappreciated biomarkers and aiming to enrich patients for response, are warranted to further advance chemoimmunotherapy in this disease. Clinical trial information: NCT03214250. [Table: see text]
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- 2022
29. CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study
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Christopher R. Cabanski, Vanessa M. Hubbard-Lucey, Zev A. Wainberg, Lacey J. Kitch, Robert A. Wolff, Gauri R. Varadhachary, Ute Dugan, Theresa LaVallee, Christine Horak, Rosemarie Mick, Cécile Alanio, Samantha Bucktrout, Justin Fairchild, Mark H. O'Hara, E. John Wherry, Andrew H. Ko, Jaclyn P. Lyman, Cheryl Selinsky, Jingying Xu, Eileen M. O'Reilly, Joyson Joseph Karakunnel, George A. Fisher, Pier Federico Gherardini, Ramy Ibrahim, Ovid C. Trifan, Osama E. Rahma, Theresa Samuel, Richard O Chen, Jacob Till, Robert H. Vonderheide, Erica L. Carpenter, and Katelyn T. Byrne
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Male ,0301 basic medicine ,medicine.medical_specialty ,Time Factors ,Paclitaxel ,Population ,Adenocarcinoma ,Deoxycytidine ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Albumins ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,CD40 Antigens ,Adverse effect ,education ,Aged ,education.field_of_study ,business.industry ,Settore BIO/11 ,Middle Aged ,Metastatic Pancreatic Adenocarcinoma ,medicine.disease ,Gemcitabine ,United States ,Pancreatic Neoplasms ,Nivolumab ,Treatment Outcome ,030104 developmental biology ,Oncology ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Cohort ,Female ,business ,Febrile neutropenia ,medicine.drug - Abstract
Summary Background Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. Methods This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov , NCT03214250 and is ongoing. Findings Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). Interpretation APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. Funding Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.
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- 2021
30. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce
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Elad Sharon, Edward Cha, Maria Libera Ascierto, Charles G. Drake, Michael A. Postow, James L. Gulley, Dung T. Le, Eric H. Rubin, Margaret K. Callahan, Ryan J. Sullivan, Vassiliki A. Papadimitrakopoulou, Harriet M. Kluger, Hussein Abdul-Hassan Tawbi, Michaela Bowden, Shilpa Gupta, David Feltquate, R. Humphrey, Janis M. Taube, Theresa LaVallee, Helen X. Chen, Vanessa M. Hubbard-Lucey, Roberta Zappasodi, Suzanne L. Topalian, Mario Sznol, and Robert L. Ferris
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0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Programmed Cell Death 1 Receptor ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Position Article and Guidelines ,Neoplasms ,medicine ,Biomarkers, Tumor ,Immunology and Allergy ,Humans ,Intensive care medicine ,RC254-282 ,Pharmacology ,business.industry ,Clinical study design ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,Immunotherapy ,medicine.disease ,Discontinuation ,Blockade ,Clinical trial ,030104 developmental biology ,Drug development ,030220 oncology & carcinogenesis ,oncology ,Molecular Medicine ,Female ,business - Abstract
As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge. To address this unmet need, the Society for Immunotherapy of Cancer convened a multistakeholder taskforce—consisting of experts in cancer immunotherapy from academia, industry, and government—to generate consensus clinical definitions for resistance to PD-(L)1 inhibitors in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. The taskforce generated consensus on several key issues such as the timeframes that delineate each type of resistance, the necessity for confirmatory scans, and identified caveats for each specific resistance classification. The goal of this effort is to provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance.
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- 2020
31. 343 Multiomic biomarker signatures identify subsets of patients who may benefit from either nivolumab or sotigalimab in combination with chemotherapy in metastatic pancreatic cancer
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Kamil Sklodowski, George A. Fisher, Jakob Vowinckel, Andrew H. Ko, Shannon Pfeiffer, Osama Rahm, Theresa LaVallee, Eileen M. O'Reilly, Lacey J. Kitch, Lukas Reiter, Robert H. Vonderheide, Roland Bruderer, Robert A. Wolff, Deena M. Maurer, Christopher R. Cabanski, Pier Federico Gherardini, Marco Tognetti, Jaclyn P. Lyman, Mark H. O'Hara, Zev A. Wainberg, Jill O'Donnell-Tormey, and Jia Xin Yu
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Pharmacology ,Oncology ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,business.industry ,T cell ,medicine.medical_treatment ,Immunology ,Population ,Immunotherapy ,medicine.anatomical_structure ,Immune system ,Cancer immunotherapy ,Internal medicine ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Biomarker (medicine) ,Nivolumab ,business ,Antigen-presenting cell ,education - Abstract
BackgroundGemcitabine/nab-Paclitaxel (GnP) is a standard of care regimen for first-line metastatic pancreatic ductal adenocarcinoma (PDAC) and has a 1-year overall survival (OS) rate of approximately 35%. There is an urgent need for novel therapeutics and precision medicine approaches in PDAC. PRINCE, a randomized phase 2 trial, reported an increased 1-year OS relative to historical data, for patients treated with nivolumab (nivo)/GnP (57.3%, p = 0.007, n=34) and sotigalimab (sotiga) (APX005M; CD40 agonist)/GnP (48.1%, p = 0.062, n= 36).MethodsTo investigate immune modulatory and pharmacodynamic (PD) effects of nivo or sotiga in combination with GnP we used several orthogonal minimally invasive, blood-based biomarker technologies. Immune population profiles were evaluated by CyTOF and features of T cell phenotype and function by multicolor flow cytometry. Soluble proteins were evaluated with predefined panels using the Olink platform (Immuno-oncology (IO) and Immune Response) along with an unbiased mass spectrometry proteomic approach (Biognosys) that identified circulating soluble proteins of significance.ResultsRelative to baseline, patients who received nivo/GnP had numerically increased frequencies of proliferating, activated CD8+ and CD4+ effector memory T cells in circulation across multiple timepoints. These patients also had significantly increased levels of soluble proteins associated with type II interferon responses and immune cell migration and T cell activation, as well as significantly decreased levels of immunomodulatory proteins.Patients who received sotiga/GnP had increased expression of the co-stimulatory molecule CD86 on conventional dendritic cells. These patients also had significantly increased concentrations of soluble proteins associated with mature antigen presenting cells, and the activation of helper CD4+ T cells, B cells, and monocytes. Significant increases in soluble proteins associated with type-1 cell-mediated effector immunity and decreases in immunosuppressive factors were observed in both arms. Significant proteins were defined as p ≤ 0.05, log2 expression fold change ≥ 0.5 (Olink) and Sparse PLS discriminant analysis was used with zero as a threshold (Biognosys).ConclusionsThis study is a first to use multiomic minimally invasive biomarker approaches in PDAC to demonstrate PD effects and immune modulation with immunotherapy/chemotherapy combinations. Orthogonal assays demonstrate that nivo/GnP and sotiga/GnP elicit unique immune responses and the observed effects are consistent with their distinct mechanisms of action. These data suggest that multiomic biomarker signatures may identify subsets of patients who may benefit from an immunotherapy/chemo approach in PDAC. Moreover, results from these analyses will support early phase clinical study development decisions.AcknowledgementsWe extend our gratitude to the patients, their families, the clinical investigators, and their site staff members who are making this trial possible. We would also like to thank Sultan Nawabi at Parker Institute for Cancer Immunotherapy (PICI) for operations leadership of the trial. We thank Bristol Myers Squibb (BMS) and Apexigen for collaboration and study drugs. The study was funded by Cancer Research Institute, BMS and PICI.Trial RegistrationNCT03214250Ethics ApprovalThis study was approved by University of Pennsylvania Institutional Review Board; Federalwide assurance #00004028.
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- 2021
32. An exploratory study of nivolumab (nivo) with or without ipilimumab (ipi) according to the percentage of tumoral CD8 cells in advanced metastatic cancer
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James P. Allison, Cheryl Selinsky, Nicholas L. Bayless, Jill O'Donnell-Tormey, Ute Dugan, Apostolia Maria Tsimberidou, Padmanee Sharma, F. Stephen Hodi, Marko Spasic, Michael Tezlaff, Shivaani Kummar, Leo Nissola, Alexandra Drakaki, David Y. Oh, Lacey J. Kitch, Jennifer C Ayran, Christopher R. Cabanski, Vanessa M. Hubbard-Lucey, Theresa LaVallee, and Danny N. Khalil
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immune checkpoint inhibitors ,Improved survival ,Cancer ,Ipilimumab ,medicine.disease ,Internal medicine ,Medicine ,In patient ,Nivolumab ,business ,CD8 ,medicine.drug - Abstract
2573 Background: Immune checkpoint inhibitors (ICIs) have demonstrated durable clinical responses and improved survival in patients (pts) across numerous indications. Despite this progress, the benefit of ICIs is limited to a minority of overall metastatic cancer patients. There is a critical need for biomarkers agnostic of tumor type to inform which pts will benefit from nivo alone versus ipi/nivo combination treatment. Both pre-treatment tumoral CD8 + cells and recruitment of CD8+ T cells in response to ICIs are associated with improved clinical outcomes in patients treated with anti-PD-1 therapy. 1,2,3,4 Here we report the final results of a prospective clinical study in which pts with varying advanced solid tumors were assigned to nivo, with or without ipi, based on the percentage of tumoral CD8 cells at the time of treatment. Methods: We performed a prospective, non-randomized, open-label, multicenter study in which pts with tumoral CD8+ cells ≥ 15% (CD8+ high) received nivo 360mg IV Q3W, followed by nivo maintenance 480mg Q4W. Pts with tumoral CD8+ cells < 15% (CD8+ low) received nivo 360 mg IV Q3W, and ipi at 1 mg/kg IV Q3W for 2 doses and then Q6W for 2 doses, followed by nivo maintenance 480 mg IV Q4W until PD or intolerable toxicity. Primary endpoints were Disease Control Rate (DCR: CR, PR, or SD ≥ 6 months) and CD8 low to high conversion (< 15% to ≥ 15%). Baseline and on-treatment tumor, blood and stool samples were collected for multiomic biomarker analyses. This study was not powered for formal statistical analysis. Up to 200 pts could be enrolled to allow for adaptive exploration of response and CD8 changes. Results: N = 79 pts were enrolled:7 in CD8+ high arm (nivo) and 72 in CD8+ low arm (ipi/nivo). The study enrolled a wide variety of primary solid tumors; the most common were gynecological (n = 15), prostate (12), and head and neck (7). DCR was 14% (1/7; 95% CI 1 - 44) and 24% (17/72; 95% CI 15 - 34) in the CD8 high and CD8 low arms, respectively. Of 39 pts in CD8 low arm with an on-treatment biopsy, 14 (36%; 95% CI 22 - 51) had CD8 conversion; 7/14 pts (50%) who converted had DCR. Immune-related AEs (irAEs) were consistent with known safety profile of both drugs. Conclusions: Ipi/nivo demonstrated clinical responses and increased CD8% in a range of “cold” tumors with low tumoral CD8 cells. There may be an association between increasing CD8% and response. Baseline high CD8% alone does not appear to be sufficient as a pan-cancer predictive biomarker of response to nivo monotherapy. CD8 conversion, response, and irAEs associated with circulating and stool-based biomarkers are under evaluation as composite biomarkers may improve their predictive value. Clinical trial information: 03651271.
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- 2021
33. Baseline level and early on-treatment clearance of circulating mutant KRAS in metastatic pancreatic ductal adenocarcinoma treated with chemotherapy with or without immunotherapy
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Lacey J. Kitch, George A. Fisher, Robert A. Wolff, Robert H. Vonderheide, Taylor A. Black, Stephanie S. Yee, Mark H. O'Hara, Andrew H. Ko, Osama E. Rahma, Eileen M. O'Reilly, Zhuoyang Wang, Theresa LaVallee, Cheryl Selinsky, Aseel Abdalla, Pier Federico Gherardini, Erica L. Carpenter, Zev A. Wainberg, Jacob Till, Jaclyn P. Lyman, and Neha Bhagwat
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Cancer Research ,Chemotherapy ,Pancreatic ductal adenocarcinoma ,business.industry ,medicine.medical_treatment ,Mutant ,Immunotherapy ,Baseline level ,medicine.disease_cause ,Oncology ,Cancer research ,Medicine ,KRAS ,business - Abstract
4122 Background: Traditional imaging-guided therapeutic decision-making for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) may lag and, on occasion, be misleading. The concept of liquid biopsy-based molecular response holds promise for proximate and accurate therapy monitoring and assessment of emerging resistance to therapy. Here we investigate the association between baseline (pre-treatment) level and early, on-treatment changes in plasma circulating cell-free DNA (ccfDNA) mutant KRAS (ctKRAS) with progression-free survival (PFS) and overall survival (OS) in mPDAC. Methods: 189 plasma samples were analyzed from 123 total patients with mPDAC. An initial cohort included 54 patients treated at the University of Pennsylvania who received first-line standard of care (SOC) regimens and had a baseline plasma sample. Of these, 21 also had an on-therapy sample collected at ̃8 weeks. We also analyzed an independent cohort of 69 patients enrolled in the PRINCE trial (NCT03214250) who had a baseline sample, of which 45 also had an on-treatment sample at ̃8 weeks. PRINCE trial patients received gemcitabine/nab-paclitaxel with immunotherapy (I/O) agents (APX005M and/or nivolumab). ctKRAS variant allele fraction (VAF) was quantified by droplet digital PCR on pre-amplified ccfDNA. Baseline ctKRAS was dichotomized at 5% VAF. ctKRAS clearance was defined as detectable ctKRAS at baseline followed by ctKRAS becoming undetectable in the on-treatment sample. Results: Baseline ctKRAS (above/below 5% VAF) and ctKRAS clearance were associated with PFS and OS in both cohorts (Table). Further, in a multivariate cox regression model, ctKRAS clearance associated with improved PFS (HR 3.8, 1.4-10.9 or 3.6, 1.8-7.2) in both the SOC and I/O cohorts, respectively, and OS in the SOC cohort (HR 5.5, 1.5-20.8) after adjusting for baseline VAF. Conclusions: Baseline ctKRAS is significantly associated with OS and PFS in mPDAC in both independent cohorts. Further, early on-treatment ctKRAS clearance is strongly associated with improved PFS and OS, independent of baseline ctKRAS VAF. These data strongly support further investigation of ccfDNA as a biomarker of response and resistance to therapy.[Table: see text]
- Published
- 2021
34. Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients
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Daniel Johnson, Erin Isaacson Wechsler, Neil E. Bhola, Noah D. Peyser, Richard C.K. Jordan, Toni M. Brand, Hua Li, Sourav Bandyopadhyay, Umamaheswar Duvvuri, Jennifer R. Grandis, Stefan Hartmann, Theresa LaVallee, Max V. Ranall, and Yan Zeng
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,Papillomavirus E7 Proteins ,Cell ,Cervical Cancer ,Receptor tyrosine kinase ,Mice ,0302 clinical medicine ,ErbB-3 ,Viral ,Molecular Targeted Therapy ,skin and connective tissue diseases ,Cancer ,Oncogene Proteins ,Human papillomavirus 16 ,Tumor ,biology ,HPV infection ,virus diseases ,female genital diseases and pregnancy complications ,Elafin ,Infectious Diseases ,medicine.anatomical_structure ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Receptor ,medicine.medical_specialty ,Oncology and Carcinogenesis ,Small Interfering ,Article ,Cell Line ,03 medical and health sciences ,Rare Diseases ,Internal medicine ,medicine ,Carcinoma ,Animals ,Humans ,Oncology & Carcinogenesis ,Dental/Oral and Craniofacial Disease ,PI3K/AKT/mTOR pathway ,Neoplastic ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,Papillomavirus Infections ,Head and neck cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Repressor Proteins ,body regions ,030104 developmental biology ,Squamous Cell ,Gene Expression Regulation ,biology.protein ,RNA ,Sexually Transmitted Infections ,business - Abstract
Purpose: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinomas (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV+ tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV+ versus HPV− tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide-3-kinase (PI3K) in HPV+ tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling and determined whether HER3 could be a molecular target in HPV+ HNSCC. Experimental Design: HER3 was investigated as a molecular target in HPV+ HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV+ and HPV− HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379. Results: HER3 was overexpressed in HPV+ HNSCC, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV+ cell lines and PDXs. Conclusions: This study uncovers a direct relationship between HPV infection and HER3 in HNSCC and provides a rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV+ patients. Clin Cancer Res; 23(12); 3072–83. ©2016 AACR.
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- 2017
35. Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma
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Veronique Neumeister, Umamaheswar Duvvuri, Diego Alvarado, Julie E. Bauman, Seungwon Kim, Jonathan R. George, Ahmed Chenna, Thomas Hawthorne, Jennifer R. Grandis, Theresa LaVallee, and Richard Gedrich
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Receptor, ErbB-3 ,Phases of clinical research ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,ErbB-3 ,Monoclonal ,Cancer ,Tumor ,Cetuximab ,Antibodies, Monoclonal ,Middle Aged ,Immunological ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Toxicity ,Female ,medicine.drug ,Receptor ,Signal Transduction ,medicine.medical_specialty ,Neuregulin-1 ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Antibodies ,Article ,03 medical and health sciences ,Rare Diseases ,Pharmacokinetics ,Clinical Research ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Oncology & Carcinogenesis ,Dental/Oral and Craniofacial Disease ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,medicine.disease ,Head and neck squamous-cell carcinoma ,Clinical trial ,030104 developmental biology ,Tumor progression ,Pharmacodynamics ,business ,Biomarkers - Abstract
Purpose: ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A “window-of-opportunity” study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC. Patients and Methods: Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed. Results: pErbB3 was detectable in all tumors prior to treatment and decreased for 10 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 27.7%–84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment–related toxicity was grade 1–2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus–negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment. Conclusions: This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.
- Published
- 2019
36. It Is a Capital Mistake to Theorize Who to Treat with Checkpoint Inhibitors before One Has Data
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Christine N. Spencer, Daniel K. Wells, and Theresa LaVallee
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0301 basic medicine ,Cancer Research ,Tumor microenvironment ,business.industry ,Immune checkpoint inhibitors ,medicine.medical_treatment ,Systemic immunity ,Mistake ,Immunotherapy ,Bioinformatics ,Metadata ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Neoplasms ,Biomarkers, Tumor ,Medicine ,Profiling (information science) ,Humans ,business - Abstract
Immunotherapy results in remarkable clinical benefit in a subset of cancer patients by activating the patient's own immune system. The factors determining which cancer patients will benefit are diverse. Success in realizing precision immunotherapy needs collaboration to bring together multiple diverse data sets. Defining multi-factorial biomarker algorithms for immunotherapy requires new approaches and methodologies that use deep molecular and cellular profiling of the tumor microenvironment, systemic immunity with clinical metadata from clinical trials, and other databases.
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- 2018
37. ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC
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Gwenda F. Ligon, Theresa LaVallee, Veronique Neumeister, David L. Rimm, Diego Alvarado, Jay S. Lillquist, Gerald McMahon, Scott Seibel, and Gerald J. Wallweber
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0301 basic medicine ,Cell signaling ,Receptor, ErbB-3 ,Receptor, ErbB-2 ,Cancer Treatment ,lcsh:Medicine ,Cetuximab ,Signal transduction ,ERK signaling cascade ,Biochemistry ,0302 clinical medicine ,Medicine and Health Sciences ,ERBB3 ,Post-Translational Modification ,Phosphorylation ,lcsh:Science ,Multidisciplinary ,Squamous Cell Carcinomas ,Signaling cascades ,Head and Neck Tumors ,ErbB Receptors ,Oncology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,EGFR signaling ,medicine.drug ,Research Article ,Cell biology ,Signal Inhibition ,Neuregulin-1 ,Antineoplastic Agents ,Carcinomas ,03 medical and health sciences ,Head and Neck Squamous Cell Carcinoma ,Amphiregulin ,ErbB ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Humans ,Cell Proliferation ,Colorectal Cancer ,Akt/PKB signaling pathway ,business.industry ,lcsh:R ,Cancers and Neoplasms ,Biology and Life Sciences ,Proteins ,medicine.disease ,Head and neck squamous-cell carcinoma ,030104 developmental biology ,Head and Neck Cancers ,Cancer research ,lcsh:Q ,business ,Biomarkers ,Transforming growth factor - Abstract
Head and neck squamous cell carcinoma (HNSCC) accounts for 3-5% of all tumor types and remains an unmet medical need with only two targeted therapies approved to date. ErbB3 (HER3), the kinase-impaired member of the EGFR/ErbB family, has been implicated as a disease driver in a number of solid tumors, including a subset of HNSCC. Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models. Surprisingly, we found that while NRG1 is required for ErbB3 activation, it was not sufficient to fully predict for KTN3379 activity. An evaluation of HNSCC patient samples demonstrated that NRG1 expression was significantly associated with expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα). Furthermore, NRG1-positive HNSCC cell lines that secreted high levels of AREG and TGFα or contained high levels of EGFR homodimers (H11D) demonstrated a better response to KTN3379. Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC.
- Published
- 2017
38. Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer
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Theresa LaVallee, Nevan J. Krogan, Hua Li, Max V. Ranall, Yan Zeng, Stefan Hartmann, Carolyn Kemp, Margaret Soucheray, Daniel Johnson, Neil E. Bhola, Jennifer R. Grandis, Julie E. Bauman, Toni M. Brand, Sourav Bandyopadhyay, Michelle A. Ozbun, Umamaheswar Duvvuri, and Rachel A. O'Keefe
- Subjects
0301 basic medicine ,Cancer Research ,Receptor, ErbB-3 ,Papillomavirus E7 Proteins ,Cell ,Cervical Cancer ,medicine.disease_cause ,Receptor tyrosine kinase ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,ErbB-3 ,Viral ,Receptor ,Cancer ,Phosphoinositide-3 Kinase Inhibitors ,Oncogene Proteins ,Tumor ,biology ,Infectious Diseases ,medicine.anatomical_structure ,Oncology ,5.1 Pharmaceuticals ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Development of treatments and therapeutic interventions ,Protein Binding ,Signal Transduction ,medicine.drug_class ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Monoclonal antibody ,Article ,Cell Line ,03 medical and health sciences ,Rare Diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Oncology & Carcinogenesis ,Dental/Oral and Craniofacial Disease ,PI3K/AKT/mTOR pathway ,Animal ,business.industry ,Head and neck cancer ,Oncogene Proteins, Viral ,medicine.disease ,Xenograft Model Antitumor Assays ,Repressor Proteins ,Disease Models, Animal ,030104 developmental biology ,Cell culture ,Disease Models ,biology.protein ,Cancer research ,Sexually Transmitted Infections ,business ,Carcinogenesis - Abstract
Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors.Significance: These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. Cancer Res; 78(9); 2383–95. ©2018 AACR.
- Published
- 2017
39. KTN0158, a humanized anti-KIT monoclonal antibody, demonstrates biologic activity against both normal and malignant canine mast cells
- Author
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Linda Crew, Andrew J. Garton, Sarah B. Rippy, Cheryl A. London, Gerald McMahon, Richard Gedrich, Lori Lopresti-Morrow, Theresa LaVallee, Krista M. D. La Perle, Heather L. Gardner, and G. S. Post
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,Monoclonal antibody ,Article ,03 medical and health sciences ,0302 clinical medicine ,Dogs ,medicine ,Animals ,Humans ,Dog Diseases ,Mast Cells ,Phosphorylation ,Cell Proliferation ,biology ,Cell growth ,business.industry ,Degranulation ,Cancer ,Antibodies, Monoclonal ,Mast cell ,medicine.disease ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Immunology ,Mutation ,biology.protein ,Cancer research ,Histopathology ,Female ,Antibody ,business - Abstract
Purpose: KTN0158 is a novel anti-KIT antibody that potently inhibits wild-type and mutant KIT. This study evaluated the safety, biologic activity, and pharmacokinetic/pharmacodynamics profile of KTN0158 in dogs with spontaneous mast cell tumors (MCT) as a prelude to human clinical applications. Experimental Design: Cell proliferation, KIT phosphorylation, and mast cell degranulation were evaluated in vitro. KTN0158 was administered to 4 research dogs to assess clinical effects and cutaneous mast cell numbers. Thirteen dogs with spontaneous MCT were enrolled into a prospective phase I dose-escalating open-label clinical study of KTN0158 evaluating 3 dose levels and 2 schedules and with weekly assessments for response and clinical toxicities. Results: KTN0158 was a potent inhibitor of human and dog KIT activation and blocked mast cell degranulation in vitro. In dogs, KTN0158 was well tolerated and reduced cutaneous mast cell numbers in a dose-dependent manner. Clinical benefit of KTN0158 administration in dogs with MCT (n = 5 partial response; n = 7 stable disease) was observed regardless of KIT mutation status, and decreased KIT phosphorylation was demonstrated in tumor samples. Histopathology after study completion demonstrated an absence of neoplastic cells in the primary tumors and/or metastatic lymph nodes from 4 dogs. Reversible hematologic and biochemical adverse events were observed at doses of 10 and 30 mg/kg. The MTD was established as 10 mg/kg. Conclusions: KTN0158 inhibits KIT phosphorylation, demonstrates an acceptable safety profile in dogs, and provides objective responses in canine MCT patients with and without activating KIT mutations, supporting future clinical evaluation of KTN0158 in people. Clin Cancer Res; 23(10); 2565–74. ©2016 AACR.
- Published
- 2016
40. Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression
- Author
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Lori Lopresti-Morrow, Theresa LaVallee, Andrew Garton, E. Sergio Trombetta, Shannon Pankratz, Linda Crew, Neal Janson, Richard Gedrich, Scott Seibel, and Sreekala Mandiyan
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,Cancer Research ,medicine.drug_class ,Population ,Programmed Cell Death 1 Receptor ,CD8-Positive T-Lymphocytes ,Monoclonal antibody ,Receptor tyrosine kinase ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,medicine ,Animals ,Humans ,CTLA-4 Antigen ,Phosphorylation ,Cytotoxicity ,education ,Immunosuppression Therapy ,education.field_of_study ,Innate immune system ,biology ,Myeloid-Derived Suppressor Cells ,Antibodies, Monoclonal ,Drug Synergism ,Cell Cycle Checkpoints ,Xenograft Model Antitumor Assays ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Colonic Neoplasms ,Cancer research ,biology.protein ,Antibody ,Tyrosine kinase - Abstract
The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types, including gastrointestinal stromal tumors, in which constitutively active mutant forms of KIT represent an actionable target for small-molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for antitumor effects of an inhibitory KIT mAb, dosed either alone or in combination with immune checkpoint inhibitors. Anti-KIT mAb treatment enhanced the antitumor activity of anti–CTLA-4 and anti–PD-1 mAbs, and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell population and by restoring CD8+ and CD4+ T-cell populations to levels observed in naïve mice. These data provide a rationale for clinical investigation of the human KIT-specific mAb KTN0158 in novel immuno-oncology combinations with immune checkpoint inhibitors and other immunotherapeutic agents across a range of tumor types. Mol Cancer Ther; 16(4); 671–80. ©2017 AACR.
- Published
- 2016
41. Abstract CT004: A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients
- Author
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Andrew H. Ko, Jaclyn P. Lyman, Theresa LaVallee, Mick Rosemarie, Travis J. Hollmann, Osama E. Rahma, Zev A. Wainberg, Gauri R. Varadhachary, Lacey J. Kitch, Ute Dugan, Erica L. Carpenter, Cheryl Selinsky, Pier Federico Gherardini, Mark H. O'Hara, Ovid C. Trifan, George A. Fisher, Robert H. Vonderheide, Eileen M. O'Reilly, Christopher R. Cabanski, and Vanessa M. Hubbard-Lucey
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Phases of clinical research ,Neutropenia ,01 natural sciences ,010104 statistics & probability ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,0101 mathematics ,education ,education.field_of_study ,Chemotherapy ,business.industry ,medicine.disease ,Gemcitabine ,Adenocarcinoma ,Nivolumab ,business ,Febrile neutropenia ,medicine.drug - Abstract
Background: Checkpoint inhibitors such as anti-PD-1 are ineffective as single agents for patients (pts) with PDAC. Preclinical data suggest that chemotherapy with agonistic CD40 antibodies can be combined with anti-PD-1 to trigger effective T cell immunity. We conducted a multi-center, open label clinical trial to evaluate the combination of APX005M with nivo and standard chemotherapy (gem and NP). Herein, we report safety and efficacy from the ongoing study. Methods: Pts with previously untreated PDAC were enrolled in 4 cohorts: Gem/NP/APX005M 0.1 mg/kg (B1), Gem/NP/APX005M 0.3 mg/kg (B2), Gem/NP/Nivo/APX005M 0.1 mg/kg (C1) and Gem/NP/Nivo/APX005M 0.3 mg/kg (C2). Primary objectives were to evaluate safety and determine the recommended Phase II dose (RP2D) of APX005M. Secondary objectives included tumor response and immune pharmacodynamics. Analyses were performed on dose-limiting toxicity (DLT)-evaluable subjects, defined as receiving 1 dose of APX005M and ≥ 2 doses of gem/NP during Cycle 1 and remaining on study through Cycle 2 Day 1. Results: N=30 pts dosed; 24 DLT-evaluable (6 per cohort). Median follow up is 32.2 weeks. N=13 (54%) pts experienced an AE leading to discontinuation, and 10 (42%) pts experienced a treatment-related serious AE. Two DLTs were observed, 1 each in cohorts B2 and C1 (grade 3 and 4 febrile neutropenia, respectively). AE rates were similar across cohorts. Four (17%) subjects died (2 each in Cohorts B1 and C1) due to disease progression (n=2) and AE (n=2, sepsis and septic shock in the setting of neutropenia). Within the DLT-evaluable population, best overall responses included 14 (58%) PR (11 confirmed, 3 unconfirmed), 8 (33%) SD, 1 (4%) PD and 1 (4%) NE. Post-baseline tumor assessments were available for 2 of the 6 DLT-inevaluable pts (best overall responses of SD and confirmed PR). Multiplexed IHC analysis of baseline tumors revealed a low CD8 T cell and high macrophage infiltrate. Analysis of circulating mutant KRAS DNA showed marked and rapid decrease with therapy in some pts. Immune profiling of PBMCs at baseline and on-treatment by CyTOF revealed remodeling of the myeloid compartment in response to treatment, with rapid activation of dendritic cells in most pts. Conclusions: Gem/NP/APX005M ± nivo demonstrated manageable safety profiles and promising antitumor activity in untreated metastatic PDAC pts. APX005M 0.3 mg/kg was selected as the dose for a randomized Phase II study in which the primary endpoint is 1-year overall survival. Clinical trial information: NCT02482168. Citation Format: Mark H. O'Hara, Eileen M. O'Reilly, Mick Rosemarie, Gauri Varadhachary, Zev A. Wainberg, Andrew Ko, George A. Fisher, Osama Rahma, Jaclyn P. Lyman, Christopher R. Cabanski, Erica L. Carpenter, Travis Hollmann, Pier Federico Gherardini, Lacey Kitch, Cheryl Selinsky, Theresa LaVallee, Ovid C. Trifan, Ute Dugan, Vanessa M. Hubbard-Lucey, Robert H. Vonderheide. A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT004.
- Published
- 2019
42. Stool donor qualification and collection from metastatic melanoma (MM) patients (pts) who have responded to checkpoint inhibitors (CPI) for manufacturing of fecal microbiota transplantation (FMT)
- Author
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John Aunis, Jennifer Mahoney, Ramy Ibrahim, Lata Jayaraman, Hussein Abdul-Hassan Tawbi, Jennifer A. Wargo, David A. Cook, Theresa LaVallee, Elizabeth M. Burton, Isabella C. Glitza, Jennifer R. Wortman, and Kevin Litcofsky
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Metastatic melanoma ,business.industry ,Internal medicine ,Immune checkpoint inhibitors ,medicine ,Single agent ,Fecal bacteriotherapy ,business - Abstract
TPS146 Background: There have been remarkable improvements in responses rates (RR) and outcomes for pts with MM with the use of single agent CPIs. However, only 35% of pts respond to therapy and less than 10% achieve a complete response (CR). Although CPIs are approved for advanced MM treatment, there is a critical need to identify predictors of response and improve outcomes for these pts, the majority of whom will die from their disease. In an analysis of stool from MM pts prior to receiving CPI (anti-PD1), MD Anderson reported the association of higher alpha diversity and a favorable “Type I” signature with improved RR and prolonged PFS. Subsequently, FMT in mice via oral gavage using stool from CR MM pts responding to anti-PD1 with a favorable microbiome signature and treated with CPI demonstrated improved RR compared to FMT with stool from non-responders. Although FMT has been studied and has shown efficacy in other diseases, clinical safety and utility in pts with MM requires investigation. We hypothesize that FMT from MM pts with CR to CPIs and a Type I signature will be tolerable and demonstrate favorable outcomes. Methods: To initiate the testing of this hypothesis, we designed a study to identify and screen pts with MM who have responded to anti-PD1 for FMT stool donation. Pts must be in CR from MM for 6 months on 2 consecutive scans. Screening procedures per standard practice of approved INDs for FMT include health history questionnaires, physical exam, confirmation of current disease status, infectious disease screening, and an evaluation of the stool sample to ensure Type I signature requirements. Notably, there have been specific modifications made to this protocol in donor eligibility criteria, as accepted by the FDA, to accommodate this unique patient population. Participants will donate stool for up to 4 weeks and may be considered for subsequent donation cycles after undergoing re-screening. Stool will be manufactured into capsule form and used in the clinical trial. This study is open and active at three sites, MD Anderson, MGH, and DFCI.
- Published
- 2019
43. Pharmacokinetic and Pharmacodynamic Comparability Study of Moxetumomab Pasudotox, an Immunotoxin Targeting CD22, in Cynomolgus Monkeys
- Author
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Bettina Donato-Weinstein, Kamille O'Connor, Theresa LaVallee, Zhenling Yao, Feng Jin, Inna Vainshtein, Laurie Iciek, Amy Schneider, Meina Liang, Lorin Roskos, Mikhail Zusmanovich, Rozanne Lee, and Bing Wang
- Subjects
Cell Survival ,Sialic Acid Binding Ig-like Lectin 2 ,Lymphocyte ,Bacterial Toxins ,Population ,Exotoxins ,Pharmaceutical Science ,Antineoplastic Agents ,Bioequivalence ,Pharmacology ,Models, Biological ,Lymphocyte Depletion ,Moxetumomab pasudotox ,Pharmacokinetics ,Immunotoxin ,medicine ,Animals ,Lymphocyte Count ,education ,Feedback, Physiological ,B-Lymphocytes ,education.field_of_study ,Models, Statistical ,business.industry ,Immunotoxins ,Macaca fascicularis ,medicine.anatomical_structure ,Pharmacodynamics ,Injections, Intravenous ,Bone marrow ,business - Abstract
Moxetumomab pasudotox is an immunotoxin currently being investigated in patients for the treatment of CD22-expressing B-cell malignancies. A single-cycle pharmacokinetic (PK)-pharmacodynamic (PD) study was conducted in cynomolgus monkeys for PK comparability assessment and population PK-PD modeling after major manufacturing process and site changes. Primates were randomized by body weight and baseline CD22 lymphocyte counts to receive intravenous administrations of 1 mg/kg moxetumomab pasudotox (n = 12/group) on Days 1, 3, and 5. PK and B-lymphocyte count data were modeled using a population approach. The 90% confidence intervals of the geometric mean ratios of PK exposure were within the 80%-125% range. The B lymphocytes were depleted to a similar extent, and the immunogenicity incidences were similar across the two groups. The B-cell depletion was described by a novel lifespan model in which moxetumomab pasudotox induced random destruction of B cells in each aging compartment. The endogenous de novo influx from bone marrow was subject to a negative feedback mechanism. The estimated B cell apparent lifespan was 51 days. Covariate analysis confirmed that the manufacturing change had no impact on PK or PD of moxetumomab pasudotox. Results from this study supported continued clinical investigation of moxetumomab pasudotox using the new material.
- Published
- 2013
44. Targeting KIT on innate immune cells to enhance the antitumor activity of checkpoint inhibitors
- Author
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Richard Gedrich, Maximilian Stahl, Ronald Peck, Theresa LaVallee, and Joseph Paul Eder
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,Antineoplastic Agents ,Biology ,Receptor tyrosine kinase ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Costimulatory and Inhibitory T-Cell Receptors ,Neoplasms ,medicine ,Tumor Microenvironment ,Immunology and Allergy ,Animals ,Humans ,Molecular Targeted Therapy ,Tumor microenvironment ,Innate immune system ,Myeloid-Derived Suppressor Cells ,Innate lymphoid cell ,Immunotherapy ,Immunity, Innate ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Myeloid-derived Suppressor Cell ,biology.protein ,Drug Therapy, Combination ,Tumor Escape ,Nivolumab ,Signal Transduction - Abstract
Innate immune cells such as mast cells and myeloid-derived suppressor cells are key components of the tumor microenvironment. Recent evidence indicates that levels of myeloid-derived suppressor cells in melanoma patients are associated with poor survival to checkpoint inhibitors. This suggests that targeting both the innate and adaptive suppressive components of the immune system will maximize clinical benefit and elicit more durable responses in cancer patients. Preclinical data suggest that targeting signaling by the receptor tyrosine kinase KIT, particularly on mast cells, may modulate innate immune cell numbers and activity in tumors. Here, we review data highlighting the importance of the KIT signaling in regulating antitumor immune responses and the potential benefit of combining selective KIT inhibitors with immune checkpoint inhibitors.
- Published
- 2016
45. Abstract CT058: Molecular and clinical activity of CDX-3379, an anti-ErbB3 monoclonal antibody, in head and neck squamous cell carcinoma: A preoperative 'window of opportunity' study
- Author
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Seungwon Kim, Thomas Hawthorne, Jonathan R. George, Julie E. Bauman, Theresa LaVallee, Ahmed Chenna, Veronique Neumeister, Diego Alvarado, Umamaheswar Duvvuri, and Jennifer R. Grandis
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,Cetuximab ,business.industry ,Cancer ,Phases of clinical research ,medicine.disease ,Primary tumor ,Head and neck squamous-cell carcinoma ,Tumor progression ,Internal medicine ,medicine ,biology.protein ,PTEN ,Stage (cooking) ,business ,medicine.drug - Abstract
Background: ErbB3 (HER3) and its ligand, neuregulin-1 (NRG1), are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. Preclinically, treatment of primary tumor and cell line tumor models of HNSCC with CDX-3379, an anti-ErbB3 monoclonal antibody, results in significant tumor reduction and reduced tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3), and antitumor activity is enhanced when combined with cetuximab. In a Phase 1 clinical study, a patient (pt) with cetuximab- refractory HNSCC experienced a durable complete response to CDX-3379 and cetuximab. A “window-of-opportunity” study was conducted to evaluate the effect of CDX-3379 on pErbB3 and other potential tumor biomarkers in pts with HNSCC. Methods: Pts with newly diagnosed, operable HNSCC received CDX-3379 (1000 mg IV) at a 2-week interval prior to tumor resection. Pre- and post-treatment tumor samples were evaluated for expression of pErbB3 (VeraTag®); ErbB3 and NRG (quantitative in situ hybridization); and Ki67 and phosphatase and tensin homolog (PTEN) (quantitative immuno-fluorescence). Primary study objective was to demonstrate ≥ 50% reduction in pErbB3 in ≥ 30% of pts. Toxicity, pharmacokinetics, and tumor measurements were also assessed. Results: 12 pts with HNSCC (5 oral cavity, 4 oropharynx, 3 larynx; 3 HPV+, 9 HPV-; 10 stage IVA) received 2 CDX-3379 doses. Radiographic assessments and tumor resection were performed at a median (range) of 20.5 (15-26) and 27.5 (18-35) days from first CDX-3379 dose. CDX-3379 reduced pErbB3 levels in 10/12 (83%) pt samples, with ≥ 50% decreases in 7/12 (58%, P=0.04). Ki67 decreased in 5/12 (42%). In this small sample, NRG, ErbB3 or PTEN expression did not clearly correlate with changes in pErbB3, Ki67 or tumor measurements. Target trough CDX-3379 serum levels (50 µg/ml based on mouse xenograft models) were achieved in all pts. Treatment-related toxicity included diarrhea (n=6), fatigue (n=2), and acneiform dermatitis (n=2). 11/12 (92%) pts had RECIST stable disease prior to resection. A pt with HPV- HNSCC experienced significant tumor shrinkage (26% decrease in nodal metastasis radiographically; 92% in primary tumor by physical exam) on day 16, as well as marked improvement in pain and ability to eat. Tumor pErbB3 reduced from 0.45 to Conclusions: CDX-3379 is associated with molecular and clinical activity in HNSCC. CDX-3379 administration was well-tolerated and induced a significant decrease in pErbB3. In this small study of 2 CDX-3379 doses over 14 days, one pt experienced a marked clinical effect including reduced tumor size and symptomatology and 92% had RECIST stable disease pre-resection. A Phase 2 study has been initiated to evaluate the combination of CDX-3379 and cetuximab for pts with progressive HNSCC after prior cetuximab and checkpoint inhibition. Citation Format: Umamaheswar Duvvuri, Jonathan George, Seungwon Kim, Diego Alvarado, Veronique Neumeister, Ahmed Chenna, Thomas Hawthorne, Theresa LaVallee, Jennifer R. Grandis, Julie E. Bauman. Molecular and clinical activity of CDX-3379, an anti-ErbB3 monoclonal antibody, in head and neck squamous cell carcinoma: A preoperative "window of opportunity" study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT058.
- Published
- 2018
46. The hematopoietic-specific β1-tubulin is naturally resistant to 2-Methoxyestradiol and protects patients from drug-induced myelosuppression
- Author
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Daniel Escuin, James P. Snyder, Grainne Mcmahon-Tobin, Patricia Burke, Luis J Leandro-García, Yuefang Wang, Todd A. Hembrough, Ana A. Alcaraz, Paraskevi Giannakakou, Theresa LaVallee, and Cristina Rodríguez-Antona
- Subjects
Bridged-Ring Compounds ,Male ,medicine.drug_class ,Molecular Sequence Data ,Antineoplastic Agents ,Biology ,Pharmacology ,Microtubules ,Vinca alkaloid ,Mice ,Tubulin ,medicine ,Animals ,Humans ,Protein Isoforms ,Amino Acid Sequence ,Progenitor cell ,Molecular Biology ,Taxane ,Estradiol ,Stem Cells ,Cancer ,Cell Biology ,medicine.disease ,Tubulin Modulators ,2-Methoxyestradiol ,Hematopoiesis ,Mice, Inbred C57BL ,Haematopoiesis ,medicine.anatomical_structure ,biology.protein ,Systemic administration ,Taxoids ,Bone marrow ,Developmental Biology - Abstract
Taxanes and other microtubule-targeting drugs (MTDs) represent one of the most effective classes of cancer chemotherapeutics. However, ultimately their utility is limited due to drug-induced myelosuppression. Here we identify 2-Methoxyestradiol (2ME2) as the first MTD able to specifically target tumor cells while sparing the bone marrow from dose-limiting, life-threatening toxicities. Following drug selection with 2ME2, epithelial cancer cells acquired a tubulin mutation at Vbeta236I that impaired the 2ME2-tubulin interaction and rendered cells resistant to 2ME2. We further show that the hematopoietic-specific Hbeta1 tubulin isotype naturally encodes Ibeta236 and is insensitive to 2ME2. Systemic administration of 2ME2 in C57BL6 mice revealed that there was no effect on bone marrow microtubules, in contrast to the taxane or Vinca alkaloid induced toxicities. Similar results were obtained upon drug treatment of human bone marrow and CD34-positive stem/progenitor cells. Herein, we describe the first isotype-targeted chemotherapeutic, setting a new paradigm for the entire class of MTDs, and providing a model that could allow the design of new tubulin inhibitors devoid of myelosuppression. The ability to design a drug with minimal side-effects would significantly augment the chances of clinical success by allowing the use of a truly therapeutic dose rather than the maximally tolerated.
- Published
- 2009
47. Synthesis, antiproliferative, and pharmacokinetic properties of 3- and 17-double-modified analogs of 2-methoxyestradiol
- Author
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Anthony M. Treston, Gregory E. Agoston, Jamshed H. Shah, Arthur D. Hanson, Lita Suwandi, Victor S. Pribluda, Theresa LaVallee, and Xiaoguo Zhan
- Subjects
medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Phases of clinical research ,Pharmacology ,Biochemistry ,Steroid ,Mice ,Structure-Activity Relationship ,Pharmacokinetics ,In vivo ,Cell Line, Tumor ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,2-Methoxyestradiol ,Estrenes ,Cytotoxicity ,Molecular Biology ,Estradiol ,Chemistry ,Cell growth ,Organic Chemistry ,In vitro ,Rats ,Endocrinology ,Molecular Medicine ,medicine.drug - Abstract
The syntheses of 21 analogs of 2-methoxyestradiol are presented, including ENMD-1198 which was selected for advancement into Phase 1 clinical trials in oncology. These analogs were evaluated for antiproliferative activity using breast tumor MDA-MB-231 cells, for antiangiogenic activity in HUVEC proliferation assays, and for estrogenic activity in MCF-7 cell proliferation. The most active analogs were evaluated for iv and oral pharmacokinetic properties via cassette dosing in rat and in mice pharmacokinetic models.
- Published
- 2009
48. Synthesis of 2- and 17-substituted estrone analogs and their antiproliferative structure–activity relationships compared to 2-methoxyestradiol
- Author
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Theresa LaVallee, Jamshed H. Shah, Anthony M. Treston, Gregory E. Agoston, Kimberly A. Hunsucker, Xiaoguo H. Zhan, Victor S. Pribluda, Lita S. Suwandi, and Glenn M. Swartz
- Subjects
Estrone ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Cell Line ,Steroid ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,2-Methoxyestradiol ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Estradiol ,Cell growth ,Organic Chemistry ,In vitro ,Rats ,chemistry ,Microsome ,Molecular Medicine ,medicine.drug - Abstract
A novel series of 17-modified and 2,17-modified analogs of 2-methoxyestradiol (2ME2) were synthesized and characterized. These analogs were designed to retain or potentiate the biological activities of 2ME2 and have diminished metabolic liability. The analogs were evaluated for antiproliferative activity against MDA-MB-231 breast tumor cells, antiangiogenic activity in HUVEC, and estrogenic activity on MCF-7 cell proliferation. Several analogs were evaluated for metabolic stability in human liver microsomes and in vivo in a rat cassette dosing model. This study lead to several 17-modified analogs of 2ME2 that have similar or improved antiproliferative and antiangiogenic activity, lack estrogenic properties and have improved metabolic stability compared to 2ME2.
- Published
- 2009
49. Effects of Aging and Hypoxia-Inducible Factor-1 Activity on Angiogenic Cell Mobilization and Recovery of Perfusion After Limb Ischemia
- Author
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Yi Fu Zhou, Marta Bosch-Marce, Lindsey Savino, Alireza Rabi, Robert S. Kerbel, Yuval Shaked, Marianne Strazza, Youn Na, Huafeng Zhang, Sergio Rey, Theresa LaVallee, Kakali Sarkar, Gregg L. Semenza, Hiroaki Okuyama, Jacob B. Wesley, Hideo Kimura, Ye V. Liu, Scott Vandiver, and Karin R. McDonald
- Subjects
Male ,Senescence ,Aging ,medicine.medical_specialty ,Physiology ,Angiogenesis ,Genetic enhancement ,Cell ,Ischemia ,Mice, Transgenic ,Stem cell factor ,Mice ,Cell Movement ,Limb perfusion ,Animals ,Medicine ,Cells, Cultured ,Mice, Knockout ,Neovascularization, Pathologic ,business.industry ,Hypoxia (medical) ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Lower Extremity ,Reperfusion ,Cancer research ,Hypoxia-Inducible Factor 1 ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Ischemia is a stimulus for production of angiogenic cytokines that activate local vascular cells and mobilize angiogenic cells to the circulation. These responses are impaired in elderly patients with peripheral arterial disease. Hypoxia-inducible factor (HIF)-1 mediates adaptive responses to ischemia, including production of angiogenic cytokines. In this study, we demonstrate that aging and HIF-1 loss-of-function impair the expression of multiple angiogenic cytokines, mobilization of angiogenic cells, maintenance of tissue viability, and recovery of limb perfusion following femoral artery ligation. We show that HIF-1 directly activates transcription of the gene encoding stem cell factor and that mice lacking the cognate receptor C-KIT have impaired recovery from ischemia. Administration of AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, improved the recovery of perfusion in older mice to levels similar to those in young mice. Injection of AdCA5 into nonischemic limb was sufficient to increase the number of circulating angiogenic cells. These results indicate that HIF-1 activity is necessary and sufficient for the mobilization of angiogenic cells and that HIF-1α gene therapy can counteract the pathological effects of aging in a mouse model of limb ischemia.
- Published
- 2007
50. Synthesis and structure–activity relationships of 16-modified analogs of 2-methoxyestradiol
- Author
-
Gregory E. Agoston, Xiaoguo Zhan, Jamshed H. Shah, Victor S. Pribluda, Anthony M. Treston, and Theresa LaVallee
- Subjects
Stereochemistry ,medicine.medical_treatment ,Metabolite ,Clinical Biochemistry ,Glucuronidation ,Pharmaceutical Science ,Antineoplastic Agents ,Breast Neoplasms ,Biochemistry ,Chemical synthesis ,Steroid ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,2-Methoxyestradiol ,Molecular Biology ,Estradiol ,Molecular Structure ,Cell growth ,Carcinoma ,Organic Chemistry ,chemistry ,Cell culture ,Molecular Medicine ,Female ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
A series of 16-modified 2-methoxyestradiol analogs were synthesized and evaluated for antiproliferative activity toward HUVEC and MDA-MB-231 cells, and for susceptibility to conjugation. In addition, the estrogenicity of these analogs was accessed by measuring cell proliferation of the estrogen-dependent cell line MCF7 in response to compound treatment. It was observed that antiproliferative activity dropped as the size of the 16 substituent increased. Selected analogs tested in glucuronidation assays had similar rates of clearance to 2-methoxyestradiol, but had enhanced clearance in sulfonate conjugation assays.
- Published
- 2007
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