Abstract 5710: Molecular profiling of anti-PD-1 treated melanoma patients reveals importance of assessing neoantigen burden and tumor escape mechanisms for clinical treatment
Authors: Jie Wang, Sean Michael Boyle, Christina Lee, Eric Levy, Zeid Rusan, Sekwon Jang, Richard Chen
Journal: Cancer Research (2018)

Abstract Despite the remarkable response of some melanoma patients to checkpoint inhibitor therapy, significant numbers of patients do not achieve complete response. To understand this differential response, there is an increasing interest in identifying biomarkers and mechanisms that influence immunotherapy effectiveness. In this study, we characterize the immuno-genomics of tumors from a series of melanoma patients that have received anti-PD-1 checkpoint inhibitors to assess potential factors influencing response. To better understand mechanisms of anti-PD-1 response, we sequenced and genomically profiled tumors from 19 stage III and IV melanoma patients where response was evaluated using RECIST criteria. Of the 19 patients, there were 5 complete responders (CR), 8 partial responders (PR), and 6 progressive disease (PD) patients. Immuno-genomic profiling was performed using Personalis' ACE ImmunoID platform, an augmented exome/transcriptome platform and analysis pipeline that allows for assessment of tumor mutations, neoantigens, HLA typing, gene expression quantification, tumor micro-environment, and tumor escape mechanisms. The molecular information for each of the 19 melanoma patient samples was then analyzed together with the corresponding clinical response to anti-PD-1 therapy. We identified 3 outlier patients, which, while having very high neoantigen burden, did not achieve complete response (2 PR &amp; 1 PD). One of these patients had extremely high expression of IDO1, which may facilitate immune escape in a PD-1 independent manner. Two independent HLA mutations in HLA-A and HLA-B (stop-gain mutation and splice site mutation, respectively) were found in the second patient, leading to the likely loss of surface expression of two classes of HLA-A and HLA-B proteins. If these three high neoantigen burden individuals with proposed tumor escape mechanisms are removed from consideration, we found a highly significant association between neoantigen burden and response to anti-PD-1 therapy (PD + PR vs CR, P = 0.00046). We also observed that, in our cohort, response to anti-PD-1 therapy was more accurately predicted by neoantigen burden than mutational burden. In conclusion, we observed a strong correlation between response to anti-PD-1 therapy in melanoma patients and neoantigen burden when tumor escape mechanisms are considered. In our patients, we saw highly suggestive resistance mechanisms that involve perturbations to elements of the antigen presenting machinery and checkpoint blockade. This highlights the potential importance of broad immuno-genomic profiling of patients that are candidates for receiving immunotherapy. We are continuing to increase our cohort size to observe both how well the neoantigen burden holds to anti-PD-1 response and to identify additional mechanisms for immune evasion. Citation Format: Jie Wang, Sean Michael Boyle, Christina Lee, Eric Levy, Zeid Rusan, Sekwon Jang, Richard Chen. Molecular profiling of anti-PD-1 treated melanoma patients reveals importance of assessing neoantigen burden and tumor escape mechanisms for clinical treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5710.