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

• DOI: 10.1126/scitranslmed.aah3560
• Publication Date: 2017-03-01T19:10:25Z
• Authors: Whijae Roh; Pei-Ling Chen; Alexandre Reuben; Christine N. Spencer; Peter A. Prieto; John P. Miller; Vancheswaran Gopa...; Feng Wang; Zachary A. Cooper; Sangeetha M. Reddy; Curtis Gumbs; Latasha Little; Qing Chang; Wei-Shen Chen; Khalida Wani; Mariana Petaccia ...; Eveline Chen; Jacob L. Austin-B...; Hong Jiang; Jason Roszik; Michael T. Tetzlaff; Michael A. Davies; Jeffrey E. Gershe...; 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
• Keywords: Immune checkpoint; CTLA-4

Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms resistance remain incompletely understood. To address this, we recently studied a cohort melanoma patients treated with sequential against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) identified immune markers resistance. Building on these studies, performed deep molecular profiling including cell receptor sequencing whole-exome within the same demonstrated that more clonal repertoire was predictive to PD-1 but not CTLA-4 blockade. Analysis CNAs higher burden copy number loss nonresponders found it associated decreased expression genes immune-related pathways. The effect mutational load nonredundant, suggesting potential utility combinatorial biomarker optimize patient care therapy.