Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance

Whijae Roh, Pei Ling Chen, Alexandre Reuben, Christine N. Spencer, Peter A. Prieto, John P. Miller, Vancheswaran Gopalakrishnan, Feng Wang, Zachary A. Cooper, Sangeetha M. Reddy, Curtis Gumbs, Latasha Little, Qing Chang, Wei Shen Chen, Khalida Wani, Mariana Petaccia De Macedo, Eveline Chen, Jacob L. Austin-Breneman, Hong Jiang, Jason RoszikMichael T. Tetzlaff, Michael A. Davies, Jeffrey E. Gershenwald, Hussein Tawbi, Alexander J. Lazar, Patrick Hwu, Wen Jen Hwu, Adi Diab, Isabella C. Glitza, Sapna P. Patel, Scott E. Woodman, Rodabe N. Amaria, Victor G. Prieto, Jianhua Hu, Padmanee Sharma, James P. Allison, Lynda Chin, Jianhua Zhang, Jennifer A. Wargo, P. Andrew Futreal

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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.

Original languageEnglish (US)
Article numbereaah3560
JournalScience Translational Medicine
Volume9
Issue number379
DOIs
Publication statusPublished - Mar 1 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

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