Abstract 905: Comprehensive immunogenomic profiling of anti-PD-1 treated melanoma patients reveals subject-specific tumor escape mechanisms

Background: Despite the remarkable response of some melanoma patients to checkpoint inhibitor therapy, the majority of patients do not achieve complete response. It is of great interest to identify biomarkers and mechanisms that influence immunotherapy effectiveness. Here we apply our comprehensive tumor immunogenomics platform (ImmunoID NeXT) to identify potential biomarkers of response to checkpoint blockade therapy related to both the tumor and tumor microenvironment. Methods: We characterized the immunogenomics of 50 stage III/IV melanoma patients who have undergone anti-PD-1 therapy to assess potential factors influencing response. Tumor response to therapy was evaluated using RECIST criteria with a median follow-up of 12 months. Immuno-genomic profiling was performed using Personalis’ ImmunoID NeXT platform; an augmented exome/transcriptome platform and analysis pipeline which from a single paired tumor FFPE and normal blood sample yielded comprehensive tumor mutation information, gene expression quantification, neoantigen characterization, TCR repertoire profiling, HLA typing and tumor microenvironment profiling. The molecular information of the tumors was then analyzed together with their corresponding clinical response. Results: Through comprehensive immunogenomic profiling we demonstrated that higher TCR clonality in pre-treatment biopsy was predictive of response to PD-1 blockade, and significantly associated with improved progression free survival. We also observed increased response to anti-PD-1 treatment in patients with elevated pretreatment neoantigen burden. Further investigation of patients with high neoantigen burden and TCR clonality that failed to achieve complete response revealed potential resistance mechanisms to anti-PD-1 therapy. Specifically, we identified two patients with high expression of IDO1 or CTLA4, which may facilitate immune escape in a PD-1 independent manner. Additionally, we found two patients with mutations in their antigen presentation machinery (APM). The first patient had two independent HLA mutations in HLA-A and HLA-B, leading to the likely loss of surface expression of the proteins. In the second APM mutation patient we observed a high frequency (80% AF) frameshift variant in B2M, which potentially prevents proper HLA class I folding and antigen presentation. These APM mutations suggest reduced neoantigen presentation in these patients, which are probable mechanisms for tumor escape. Conclusions: In summary, o