Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Science translational medicine, 2017-03, Vol.9 (379)

Ort / Verlag

United States

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.