Scientific publications

Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

Riaz N (1), Havel JJ (2), Makarov V (3), Desrichard A (2), Urba WJ (4), Sims JS (3), Hodi FS (5), Martín-Algarra S (6), Mandal R (7), Sharfman WH 8, Bhatia S (9), Hwu WJ (10), Gajewski TF (11), Slingluff CL Jr (12), Chowell D (3), Kendall SM (3), Chang H (13), Shah R (2), Kuo F (14), Morris LGT (15), Sidhom JW (16), Schneck JP (16), Horak CE (13), Weinhold N (17), Chan TA (18). (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) Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR 97213, USA.
(5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
(6) Medical Oncology, Clínica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain.
(7) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
(8) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
(9) Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98105, USA.
(10) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
(11) Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
(12) Department of Surgery and University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
(13) Bristol-Myers Squibb, Princeton, NJ 08648, USA.
(14) Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
(15) 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.
(16) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
(17) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
(18) 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.

Magazine: Cell

Date: Nov 2, 2017

Medical Oncology

ABSTRACT

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.

CITATION  Cell. 2017 Nov 2;171(4):934-949.e15. doi: 10.1016/j.cell.2017.09.028

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