Journal
CANCER DISCOVERY
Volume 6, Issue 8, Pages 827-837Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-1545
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Funding
- Melanoma Research Alliance Team Science Award
- Kenedy Memorial Foundation [0727030, U54CA163125]
- STARS award
- UT Regents
- NIH [U54CA163125, 1K08CA160692-01A1, T32CA009599, T32CA163185, 2P30CA016672]
- CPRIT Graduate Scholar Award
- Conquer Cancer Foundation ASCO Young Investigator Award
- CPRIT Scholar in Cancer Research
- Cancer Prevention Research Institute of Texas [R1204]
- CPRIT [R1205 01]
- Robert Welch Distinguished University Chair [G-0040]
- Novartis/Array
- Merck
- Bristol-Myers Squibb
- GlaxoSmithKline
- MedImmune
- MD Anderson's Institutional Tissue Bank
- MD Anderson's Institutional Tissue Bank Award from the National Cancer Institute [2P30CA016672]
- University of Texas MD Anderson Cancer Center Melanoma Moon Shot Program
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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. (C) 2016 AACR.
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