Dissecting Germline Genetic Mediators of Clinical Response to Immune Checkpoint Blockade in Kidney Cancer
Abstract
FY21 KCRP Focus Area: To better understand the genetic etiology of therapeutic resistance in kidney cancer. Significance and Background: Immunotherapy has introduced a new paradigm in cancer treatment. Across several studies, patients with kidney cancer receiving immune checkpoint blockades have shown a substantial improvement in cancer-free survival and the overall outcome of cancer treatment. However, not all kidney cancer patients benefit from these immune-modulating agents, highlighting a critical need to explore molecular biomarkers that can identify cancer patients who are expected to benefit from immunotherapy. Toward that end, several genetic changes in the tumors (called somatic mutations) of patients with kidney cancer who benefited from immune checkpoint blockades have been identified as molecular determinants of exceptional response to immunotherapy. However, these somatic mutations do not provide a complete understanding of the mechanisms regulating the immune-tumor interaction, suggesting the presence of additional genetic alterations that can have clinical utility and biological relevance in kidney cancer immunotherapy. Scientific Objective and Rationale: This study aims to study the inherited genetic changes (also called germline variants) in a large cohort of over 750 patients with kidney cancer who were treated with immune checkpoint blockades. We hypothesize that the unique germline variant composition of each patient shapes the tumor evolution and influences how the tumor responds to various anti-cancer treatment modalities, including immunotherapy. To explore this hypothesis, we will leverage our computational expertise to generate a comprehensive, multi-faceted dataset of germline features in kidney cancer patients who were treated with immune checkpoint blockades. Using this unique dataset, we will investigate the association of each type of germline variants (rare, common, and non-coding) with better clinical outcomes in kidney cancer immunotherapy. Expected Outcomes and Clinical Applicability: This proposal aims to achieve several clinically focused outcomes. First, this study expands on what is known about the genetic mediators of higher sensitivity to immune checkpoint blockades and identifies one or more genes where germline variants are also associated with a better treatment outcome in kidney cancer. The findings of this study are also expected to explain why some kidney cancer patients benefit from immunotherapy, yet they do not have any of the somatic mutations that have been associated with a better response to these treatment modalities. In addition, identifying new genes contributing to greater tumor sensitivity can also highlight new mechanisms of immune-tumor interaction in kidney cancer, which can be further investigated in future studies. Importantly, the germline molecular markers, expected to be identified in this study, can inform decision-making with regard to which treatment plan is likely to be most effective in patients with advanced kidney cancer. Overall, the expected outcomes of this proposal have an immediate impact on the management of patients with cancer and can be readily translated into clinical care. Innovation: In addition to introducing a new paradigm (germline genomics) to enhance our understanding of the molecular mechanisms regulating the tumor-immune interaction and the immune cytolytic activity in ICB therapy, this study leverages the underutilized germline data of ICB-treated RCC cohorts to address clinically relevant hypotheses. This study also uniquely integrates several machine-learning, statistical, and epidemiological approaches to build a germline-inclusive clinical stratification framework in cancer immunotherapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210455
Entities
People
- Saud H Aldubayan
Organizations
- Dana–Farber Cancer Institute
- United States Army