Objectives and Rationale: The development of immunotherapy (IO) treatments for patients with advanced renal cell carcinoma (RCC) has revolutionized patient outcomes. With combination strategies, including pure IO treatments and IO combinations with other targeted agents, it is increasingly challenging for clinicians and patients to select the optimal treatment or sequencing prior to starting therapy. New clinical trials have begun exploring whether escalating or de-escalating the type or duration of IO therapy may be better for patients, yet consistently only a fraction of patients ultimately sustain long-term benefits to IO therapy. Pre-treatment biomarkers that predict the efficacy of IO agents prior to starting therapy have proven effective in other cancers but have not yet been identified reliably to help with treatment decision-making for RCC patients. Recently, the type and diversity of a patient's HLA has been shown to be associated with IO treatment response. An HLA type, commonly grouped into class I or class II, is inherited and is a frequently obtained test when matching patients for organ or stem cell transplant. As prior studies have solely focused on HLA class I diversity, we hypothesize that HLA class II diversity is associated with IO therapy response and toxicities. To study this, we will perform HLA testing of patients with clear cell and non-clear cell RCC and evaluate in parallel their tumor tissues for specific proteins important for HLA recognition to robustly assess HLA diversity as a biomarker for IO therapy.

Innovation: We will characterize tumors that harbor specific proteins to be displayed for immune system recognition and targeting and will evaluate the role of HLA diversity as a biomarker for IO therapies. HLA class II diversity has not been previously studied and we will study this in clear cell and non-clear cell RCC patients (on a clinical trial) to comprehensively evaluate the role of this biomarker for RCC immunotherapy.

PI Career Goals: The PI’s career goals are to improve the treatment and medical care for patients with advanced kidney cancers through the development of novel therapeutics and biomarker-directed strategies. In a major cancer center, where the PI is an academic oncologist, this includes performing clinical and translational research studies with a focus on developing novel treatment strategies that maximize efficacy and limit toxicities for RCC patients. This proposal builds on this goal by evaluating a specific biomarker for RCC immunotherapy and may be integrated in future clinical design and in the development of therapies whose tumors display IO resistance.

Career Development Plan: The PI will participate in several career development and research training activities that will be integral to gaining skills in becoming an independent investigator for kidney cancer. The proposal will allow the PI to (1) gain skills in data analysis for immunogenomics; (2) gain skills in computational biology and biostatistics; (3) gain skills in clinical and translational data analysis, interpretation, and presentation; and (4) expand the network of collaborators. The PI will also participate within the Academy of Kidney Cancer Investigators (AKCI) to receive external feedback and will collaborate to promote the AKCI to ensure research and study findings are widely applicable and generalizable.

Research Applicability: This goal of the project is to evaluate whether an individual's inherited genetics, which govern the immune system function, may predict the response to IO therapy in clear cell and non-clear cell RCC. Ultimately, study findings can further guide biomarker development, which can aid clinicians and patients in treatment decision-making by maximizing IO treatment outcomes while avoiding therapy if deemed futile/highly toxic. Further, by performing this study within clear cell and non-clear cell RCC, we also hope to gain and understanding of immunotherapy across all RCC populations which may be treated with IO agents. As all therapies for RCC patients contain an IO therapy backbone, there remains wide applicability for such a biomarker for all kidney cancer patients. As HLA testing is a routine laboratory assessment that can be performed at all hospitals, we anticipate that with evaluation, testing can be rapidly available and adopted into clinical practice. With new IO combinations on the horizon, uncovering the mechanisms of immune recognition may also help improve IO therapy efficacy in patients with refractory disease.

Contributions to Knowledge: This study has the potential to uncover new insights into RCC tumor biology and the immune recognition of kidney cancers. Insights can fuel biomarker efforts to develop a pre-treatment test to aid clinicians in decision-making and may impact the overall quality of life of all RCC patients (clear cell and non-clear cell RCC) by optimizing treatment outcomes.