Reverse Translating Molecular Determinants of Anti-Programmed Death 1 Immunotherapy Response in Mouse Syngeneic Tumor Models.

Autor:	Georgiev P; Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, New Jersey., Muise ES; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Linn DE; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey., Hinton MC; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey., Wang Y; Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, New Jersey., Cai M; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey., Cadzow L; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey., Wilson DC; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Sukumar S; Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, New Jersey., Caniga M; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey., Chen L; Department of Informatics IT, Merck & Co., Inc., Kenilworth, New Jersey., Xiao H; Department of Informatics IT, Merck & Co., Inc., Kenilworth, New Jersey., Yearley JH; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Sriram V; Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, New Jersey., Nebozhyn M; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Sathe M; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Blumenschein WM; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Kerr KS; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Hirsch HA; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Javaid S; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Olow AK; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Moy LY; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey., Chiang DY; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Loboda A; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Cristescu R; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Sadekova S; Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, New Jersey., Long BJ; Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey., McClanahan TK; Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey., Pinheiro EM; Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, New Jersey.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2022 Mar 01; Vol. 21 (3), pp. 427-439.
DOI:	10.1158/1535-7163.MCT-21-0561
Abstrakt:	Targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway with immunotherapy has revolutionized the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell-inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that can predict responsiveness to anti-PD-1/PD-L1 monotherapy in many tumor types. We analyzed the association between these biomarkers and the efficacy of PD-1 inhibitor in 11 commonly used preclinical syngeneic tumor mouse models using murinized rat anti-mouse PD-1 DX400 antibody muDX400, a surrogate for pembrolizumab. Response to muDX400 treatment was broadly classified into three categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune cell infiltration and activation in the tumor microenvironment of muDX400-responsive tumors. Baseline and on-treatment genomic analysis showed an association between TMB, murine T-cell-inflamed gene expression profile (murine-GEP), and response to muDX400 treatment. We extended our analysis to investigate a canonical set of cancer and immune biology-related gene signatures, including signatures of angiogenesis, myeloid-derived suppressor cells, and stromal/epithelial-to-mesenchymal transition/TGFβ biology previously shown to be inversely associated with the clinical efficacy of immune checkpoint blockade. Finally, we evaluated the association between murine-GEP and preclinical efficacy with standard-of-care chemotherapy or antiangiogenic agents that previously demonstrated promising clinical activity, in combination with muDX400. Our profiling studies begin to elucidate the underlying biological mechanisms of response and resistance to PD-1/PD-L1 blockade represented by these models, thereby providing insight into which models are most appropriate for the evaluation of orthogonal combination strategies. (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu