Critical Determinants of Response to Immunotherapy in Non-clear Cell RCC – CRITERIA

CRITERIA is a multidisciplinary translational project aimed at critical determinants of response to immunotherapy in non-clear cell renal cell carcinoma (nccRCC) subtypes. Among other well-annotated cohorts, we leverage clinical samples and data from the European academic SUNNIFORECAST trial (NCT03075423), the largest randomized phase II nccRCC trial worldwide. SUNNIFORECAST was an exceptionally well-designed study, including reference pathology for all cases and monitoring of data quality, and demonstrated a significant survival benefit of nivolumab and ipilimumab over standard-of-care therapies. CRITERIA will build on this unique resource to pinpoint genetic, epigenetic, tumor microenvironmental and systemic microbiota antigen factors that impact treatment response.
To elucidate key biological mechanisms driving differential responses to immunotherapy, we propose a multidimensional approach that incorporates 1] genetic and epigenetic profiles of tumor tissues at high resolution, including DNA and RNA sequencing and miRNA profiling, 2] cutting-edge technologies such as multiplex immunohistochemistry (IHC) and spatial transcriptomics to characterize composition and spatial distribution of components of the tumor microenvironment and 3] AI-accessible histomorphological tissue phenotypes associated with clinical outcome to specific treatments. In parallel, blood-based analyses of circulating tumor RNA and serum (miRNAs, cytokines, chemokines, metabolic enzymes and microbiote profiles) will scrutinize the utility of systemic changes as predictors of tumor response and survival. Notably, these efforts extends across nccRCC variants with differing aggressiveness available within the consortium, altogether systematically building a better understanding of nccRCC biology to unveil novel determinants of immunotherapy response.
CRITERIA thereby aims to contribute to the growing field of precision oncology and drive the development of biomarkers for personalized treatments.