Abstract 2512: A comprehensive genomics platform for precision immunotherapy: Simultaneously characterizing the tumor and tumor microenvironment from a single FFPE sample
Authors: Richard O. Chen
Journal: Cancer Research (2019)

Abstract Immuno-genomic profiling of the tumor and the tumor microenvironment (TME) is critical for identifying new biomarkers of immunotherapy response, understanding resistance, and enabling personalized immunotherapies. However, running a comprehensive array of biomarker assays for each patient sample is often impractical given limited tumor sample, processing complexity, and prohibitive cost. To address these challenges, we developed ImmunoID NeXT, a novel, augmented exome and transcriptome based diagnostic platform that simultaneously characterizes the tumor and TME from a single FFPE sample. We co-optimized the design of our sequencing assays and analytics to increase performance for detecting somatic mutations across ~20,000 genes, neoantigens, expression signatures, HLA-typing, T-cell receptor (TCR) and B-cell receptor repertoire, oncoviruses, tumor infiltrating lymphocytes (TILs), clinically actionable mutations, tumor mutational burden (TMB), and MSI status. We developed novel methods to sequence difficult regions of the exome and to extend coverage to key immuno-genomic biomarkers. Analytic pipelines were designed to utilize assay optimizations to achieve higher accuracy than achievable with other platforms. We then validated ImmunoID NeXT for diagnostic and therapeutic use. With a minimum of 50ng of DNA per FFPE sample and co-extracted RNA, ImmunoID NeXT completely covers between 17% to 40% more genes compared to a non-augmented exome, thus increasing sensitivity to somatic mutations and putative neoantigens. For neoantigen performance, we generated immuno-peptidomic data from mono-allelic HLA transfected cell-lines and trained neural networks to predict neoepitope binding to MHC, demonstrating a higher precision (0.88) across alleles than publicly available tools (&amp;lt;0.7). For TCR clone abundance in tumor samples, we demonstrate strong correlation with a stand-alone TCR panel results (R2&amp;gt;0.94). For TILs, we developed signatures for CD4, CD8 T-cells, and other immune cells, demonstrating concordance with synthetic and CyTOF-derived validation sets. For HLA-typing, we achieve an accuracy of 99.1% for HLA Class I, and 95% for HLA Class II typing calls. We demonstrate sensitive detection of HPV, EBV, HCV, HTLV-1, and KSHV in known samples, and accurate MSI and TMB assessment. Finally, for diagnostic reporting, we achieve high sensitivity and specificity for clinically reportable mutations comparable to diagnostic cancer panels. We have developed a novel immuno-genomics platform, ImmunoID NeXT, that can characterize both the tumor and TME from a single sample. By co-optimizing our assay and analytics for immuno-oncology, we enhance biomarker sensitivity compared to non-optimized genomics assays. Validation of the ImmunoID NeXT platform extends its use to diagnostics and personalized immunotherapies. Citation Format: Richard O. Chen. A comprehensive genomics platform for precision immunotherapy: Simultaneously characterizing the tumor and tumor microenvironment from a single FFPE sample [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2512.