Riaz et al. examined the effects of 4 weeks of nivolumab therapy in ipilimumab (IPI)-naïve or -progressor patients stratified according to good or poor response to nivolumab. In responding patients, mutation and neoantigen load contracted, presumably due to therapy-induced immunoediting, and the intratumoral TCR repertoire expanded in number (IPI-progressors) or became more unequally distributed (IPI-naïve), suggesting antigen-driven changes in the T cell population.
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.
Author Info: (1) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Cent
Author Info: (1) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (5) Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR 97213, USA. (6) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (8) Medical Oncology, Clinica Universidad de Navarra, Instituto de Investigacion Sanitaria de Navarra, 31008 Pamplona, Spain. (9) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (10) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (11) Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98105, USA. (12) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (13) Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. (14) Department of Surgery and University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. (15) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (16) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (17) Bristol-Myers Squibb, Princeton, NJ 08648, USA. (18) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (19) Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (20) Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (21) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. (22) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. (23) Bristol-Myers Squibb, Princeton, NJ 08648, USA. (24) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: weinholn@mskcc.org. (25) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: chant@mskcc.org.
