MHC-1 genotype as a predictor of response to immunotherapy.

Abstract

149 Background: MHC-1 molecules present intracellular peptides on the surface of tumor cells for recognition by CD8+ cytotoxic T-cells. Cancers with a high tumor mutational burden (TMB) are more likely to respond to immune checkpoint blockade (ICB) due to the increased chance of having a mutated peptide presented by MHC-1. However, the interaction between TMB and patient-specific MHC-1 and ICB response is unknown. Methods: We analyzed 83 patients with diverse solid tumors treated with ICB for TMB and MHC-1 (tissue next generation sequencing (NGS) (Foundation Medicine)). TMB low vs high were defined as <20 vs ≥20 mut/mb, respectively. Patient Harmonic-mean Best Rank (PHBR) (Marty et al. 2018) scores the ability of the MHC-I of an individual to bind and present a specific missense mutation. Patients were assigned the PHBR of their best presented missense driver mutation. PHBR low (strong presentation) vs high (weak presentation) were defined as <1.01 vs ≥1.01 respectively (cutoff per a receiver operator curve). Overall response rate (ORR) (includes stable disease for ≥6 months) was determined (RECIST criteria). Results: The ORR, PFS, and OS for patients treated with ICB with PHBR low vs. high tumors was 72% vs 28% (P = 0.01), 6.3 vs 4.1 months (P = 0.03), and 37.1 vs 13.9 months (P = 0.25), respectively. The ORR, PFS, and OS for TMB low vs high was 36% vs 67% (P = 0.02), 4.3 vs 14.1 months (P = 0.01), and 12.0 months vs not reached (P = 0.03), respectively. The ORR, PFS, and OS for TMB high/PHBR high vs TMB high/PHBR low was 38% vs 85% (P < 0.01), 3.9 vs 26.8 months (P <0.01), and 17.1 vs not reached (P = 0.02), respectively Conclusions: MHC-1 genotype and the ability to present driver neo-antigens predicts which patients with TMB high will respond to ICB.[Table: see text]