1. Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade
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Christine N. Spencer, Michael A. Davies, Victor G. Prieto, Khalida Wani, Sapna Pradyuman Patel, Adi Diab, Ignacio I. Wistuba, Hong Jiang, Isabella C. Glitza, Zachary A. Cooper, Padmanee Sharma, Alexandre Reuben, Lynda Chin, Lawrence N. Kwong, Sangeetha M. Reddy, Lauren E. Haydu, Pei Ling Chen, Jorge Blando, Jacob Austin-Breneman, Qing Chang, Arlene H. Sharpe, Patrick Hwu, Michael T. Tetzlaff, Jeffrey E. Gershenwald, Vancheswaran Gopalakrishnan, Peter A. Prieto, Roland L. Bassett, Wencai Ma, Luis M Vence, Wei Shen Chen, Jianhua Hu, James P. Allison, Mariana Petaccia de Macedo, Alexander J. Lazar, Rodabe N. Amaria, R. Eric Davis, Wen-Jen Hwu, Willem W. Overwijk, Russell J. Broaddus, P. Andrew Futreal, Scott E. Woodman, Jennifer A. Wargo, John P. Miller, and Whijae Roh
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0301 basic medicine ,Biopsy ,Programmed Cell Death 1 Receptor ,Antineoplastic Agents ,chemical and pharmacologic phenomena ,Article ,B7-H1 Antigen ,Immunomodulation ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,T-Lymphocyte Subsets ,Neoplasms ,medicine ,Cluster Analysis ,Humans ,CTLA-4 Antigen ,Molecular Targeted Therapy ,Melanoma ,Tumor microenvironment ,biology ,Gene Expression Profiling ,Antibodies, Monoclonal ,Cancer ,Prognosis ,medicine.disease ,Immunohistochemistry ,Immune checkpoint ,Blockade ,Treatment Outcome ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Cancer research ,Immunotherapy ,Antibody ,Biomarkers - Abstract
Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte–associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified. Significance: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827–37. ©2016 AACR. See related commentary by Teng et al., p. 818. This article is highlighted in the In This Issue feature, p. 803
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- 2016
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