@article{d3fde8bcbb454c65b42b9d2187efe76e,
title = "Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance",
abstract = "Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.",
author = "Whijae Roh and Chen, {Pei Ling} and Alexandre Reuben and Spencer, {Christine N.} and Prieto, {Peter A.} and Miller, {John P.} and Vancheswaran Gopalakrishnan and Feng Wang and Cooper, {Zachary A.} and Reddy, {Sangeetha M.} and Curtis Gumbs and Latasha Little and Qing Chang and Chen, {Wei Shen} and Khalida Wani and {De Macedo}, {Mariana Petaccia} and Eveline Chen and Austin-Breneman, {Jacob L.} and Hong Jiang and Jason Roszik and Tetzlaff, {Michael T.} and Davies, {Michael A.} and Gershenwald, {Jeffrey E.} and Hussein Tawbi and Lazar, {Alexander J.} and Patrick Hwu and Hwu, {Wen Jen} and Adi Diab and Glitza, {Isabella C.} and Patel, {Sapna P.} and Woodman, {Scott E.} and Amaria, {Rodabe N.} and Prieto, {Victor G.} and Jianhua Hu and Padmanee Sharma and Allison, {James P.} and Lynda Chin and Jianhua Zhang and Wargo, {Jennifer A.} and Futreal, {P. Andrew}",
note = "Funding Information: J.A.W. acknowledges the Melanoma Research Alliance Team Science Award, the Kenedy Memorial Foundation grant #0727030, U54CA163125, the Rising STARs (Science and Technology Acquisition and Retention) award of the University of Texas System Board of Regents, Regents' Health Research Scholar Award of the University of Texas System Board of Regents, and the generous philanthropic support of several families whose lives have been affected by melanoma. This work was supported by NIH grants 1K08CA160692-01A1 (to J.A.W.), U54CA163125 (to Z.A.C., J.A.W., and L.C.), T32CA009599 (to PAP.), T32CA163185 (to P.-L.C. and W.-S.C), NIH T32 CA009666 (to S.M.R.), and R01 CA187076-02 (to M.A.D. and P.H.). J.P.A., P.S., and JAW. are members of the Parker Institute for Cancer Immunotherapy at the MD Anderson Cancer Center. W.R. was supported by the Cancer Prevention Research Institute of Texas (CPRIT) Graduate Scholar Award. I.C.G. holds a Conquer Cancer Foundation of American Society of Clinical Oncology Young Investigator Award. L.C. is a CPRIT Scholar in Cancer Research and was supported by a grant from the CPRIT (R1204). P.A.F. holds CPRIT funding (R1205 01), a Robert Welch Distinguished University Chair (G-0040), and STARs (Science and Technology Acquisition and Retention) award of the University of Texas System Board of Regents. R.N.A. has received research support from Merck, Novartis/Array, and Bristol-Myers Squibb. W.-J.H. has received research support from Bristol-Myers Squibb, Merck, GlaxoSmithKline (GSK), and MedImmune. This work was supported by MD Anderson's Institutional Tissue Bank Award (2P30CA016672) from the National Cancer Institute. This study was also supported by philanthropic contributions to the UT MD Anderson Cancer Center Melanoma Moon Shot Program and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Publisher Copyright: {\textcopyright} 2017 The Authors, some rights reserved.",
year = "2017",
month = mar,
day = "1",
doi = "10.1126/scitranslmed.aah3560",
language = "English (US)",
volume = "9",
journal = "Science translational medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "379",
}