Prediction of immunotherapy response in deficient mismatch repair colorectal cancers using an immune-enhanced exome and transcriptome platform.

270 Background: While immune checkpoint blockade (ICB) is used to treat metastatic deficient mismatch repair (dMMR) colorectal cancers (CRCs), such tumors are heterogeneous and resistance to ICB is frequent. To date, biomarkers that can consistently predict patient response to ICB are lacking. We determined whether biomarkers that integrate tumor and immune-related molecular mechanisms could predict ICB response. Methods: Consecutive patients with metastatic dMMR CRCs (N=32) who had been treated with anti-PD-1 therapy were profiled using a validated immune-enhanced exome and transcriptome platform (ImmunoID NeXT, Personalis) using tumor and paired normal tissue. This platform provides antigen-specificity of T or B cells, indicated by the TCR or BCR respectively, neoantigen prediction, tumor mutation burden (TMB), immune profile, HLA allele-specific loss of heterogeneity (LOH) and a Neoantigen Presentation Score (NEOPS) that combines a neoantigen prediction tool with mechanisms of immune evasion. Tumor variables were analyzed in relationship to objective tumor response, and a Cox proportional hazards model was fit to predict progression-free survival (PFS) or overall survival (OS). Results: In CRCs, TCR and BCR repertoire diversity were each significantly increased in tumors from responders versus those with stable or progressive disease after anti-PD-1 treatment (p=0.015 and p=0.048, respectively). Neoantigen burden score, TMB, and HLA allele-specific LOH (reflects loss of antigen presentation machinery) were each unable to distinguish responders from nonresponders. An immune checkpoint gene expression signature was increased in nonresponders relative to responders (P= 0.005). Neoantigen presentation score (NEOPS) was prognostic when adjusted for tumor grade only for OS (p=0.048). Conclusions: The T-cell and B-cell receptor (TCR/BCR) repertoire, as well as NEOPS, were each significantly predictive of favorable response to anti-PD-1 therapy in dMMR tumors. In addition, an immune checkpoint gene expression signature was predictive of resistance to ICB.