Prediction of Immunotherapy Response in Melanoma through Combined Modeling of Neoantigen Burden and Immune-Related Resistance Mechanisms.

Autor:	Abbott CW; Personalis, Inc., Menlo Park, California., Boyle SM; Personalis, Inc., Menlo Park, California., Pyke RM; Personalis, Inc., Menlo Park, California., McDaniel LD; Personalis, Inc., Menlo Park, California., Levy E; Personalis, Inc., Menlo Park, California., Navarro FCP; Personalis, Inc., Menlo Park, California., Mellacheruvu D; Personalis, Inc., Menlo Park, California., Zhang SV; Personalis, Inc., Menlo Park, California., Tan M; Personalis, Inc., Menlo Park, California., Santiago R; Personalis, Inc., Menlo Park, California., Rusan ZM; Personalis, Inc., Menlo Park, California., Milani P; Personalis, Inc., Menlo Park, California., Bartha G; Personalis, Inc., Menlo Park, California., Harris J; Personalis, Inc., Menlo Park, California., McClory R; Personalis, Inc., Menlo Park, California., Snyder MP; Stanford University School of Medicine, Palo Alto, California., Jang S; Inova Medical Group, Falls Church, Virginia., Chen R; Personalis, Inc., Menlo Park, California. richard.chen@personalis.com.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Aug 01; Vol. 27 (15), pp. 4265-4276.
DOI:	10.1158/1078-0432.CCR-20-4314
Abstrakt:	Purpose: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB). Experimental Design: Tumors from a cohort of patients with late-stage melanoma ( n = 51) were profiled using an immune-enhanced exome and transcriptome platform. We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB. Results: Our neoantigen burden score, which integrates both exome and transcriptome features, more significantly stratified responders and nonresponders ( P = 0.016) than TMB alone ( P = 0.049). Extension of this model to include immune-related resistance mechanisms affecting the antigen presentation machinery, such as HLA allele-specific LOH, resulted in a composite neoantigen presentation score (NEOPS) that demonstrated further increased association with therapy response ( P = 0.002). Conclusions: NEOPS proved the statistically strongest biomarker compared with all single-gene biomarkers, expression signatures, and TMB biomarkers evaluated in this cohort. Subsequent confirmation of these findings in an independent cohort of patients ( n = 110) suggests that NEOPS is a robust, novel biomarker of ICB response in melanoma. (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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