BackgroundMultiple genomics-based biomarkers of response to immune checkpoint inhibition have been reported or proposed, including tumor mutation/neoantigen frequency, PD-L1 expression, T cell receptor repertoire clonality, interferon gene signature expression, HLA expression, and others.¹ Although genomics associations of response have been reported, the primary studies have used a variety of data generation and processing techniques. There is a need for data harmonization and assessment of generalizability of potential biomarkers across multiple datasets.MethodsWe acquired patient-level RNA sequencing FASTQ data files from 10 data sets reported in seven pan-cancer PD-1 and CTLA-4 immune checkpoint inhibition trials with matched clinical annotations.^2–7 We applied a common bioinformatics workflow for quality control, mapping to reference (STAR), generating gene expression matrices (SALMON), T cell receptor repertoire inference (MiXCR), extraction of immune gene signatures and immune subtypes,⁸ and differential gene expression analysis (DESeq2). We analyzed i) immunogenomics features proposed as biomarkers, and ii) gene expression signatures built from each trial for association with overall survival across the set of trials using univariable Cox proportional hazards regression. In all, we assessed 9 total immunogenomics features/signatures. P-values were adjusted for multiple testing using the Benjamini-Hochberg method.ResultsOf the 9 immunogenomics features assessed, cytolytic activity score and expression of the Follicular Dendritic Cell Secreted Protein gene (FDCSP) were associated with survival in two of seven studies, respectively (adjusted p < 0.05) (figure 1). No proposed biomarkers were significantly associated with survival in more than two studies. The sets of genes significantly associated with clinical benefit across the studies were highly disjoint, with only three genes significant in three studies and thirteen genes significant in two studies (figure 2). No genes were significantly associated with clinical benefit in more than three of seven studies.Abstract 75 Figure 1Association of immunogenomics features and proposed biomarkers with survival in 10 publicly available datasets from 7 clinical trials with immune checkpoint blockade. Nine immunogenomics features were tested in 10 publicly available RNAseq data sets from 7 published clinical trials with immune checkpoint blockade for their correlation with outcome. SKCM, skin cutaneous melanoma; BLCA, bladder cancer; Kidney, kidney cancer; Ureter, ureteral cancer; GBM, glioblastomaAbstract 75 Figure 2Association of gene expression of single genes with survival in 10 publicly available datasets from 7 clinical trials with immune checkpoint inhibitorsConclusionsNo proposed biomarkers were highly generalizable across studies. We expect that integrated modeling incorporating multiple immunogenomics features will be required to build a robust and generalizable biomarker for ICI response. Further work is needed to analyze determinants of response and clinical benefit.AcknowledgementsWe would like to thank SITC for funding for this work as part of the Sparkathon TimIOS collaborative project.ReferencesZappasodi R, Wolchok JD, Merghoub T. 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