Optimizing neoadjuvant/adjuvant anti-PD-1 therapy for localized Renal Cell Carcinoma

(24/30 lines) This proposal seeks to improve the management and survival of patients with localized renal cell carcinoma (RCC) at high risk of relapse by optimizing the utilization of anti-PD-1 therapy in the neoadjuvant/adjuvant settings. Despite surgical management, approximately 30% of patients with localized RCC develop metastatic disease, which remains largely incurable. Anti-PD-1-based therapies have shown efficacy in treating metastatic RCC, but inconsistent clinical trial results indicate a need for more precise patient selection for the implementation of these therapies in the neoadjuvant and adjuvant settings. Our multidisciplinary team has substantial experience in translational kidney cancer research and proposes to utilize the unique of collection of tissue and blood/plasma specimens from the EA8143 PROSPER (NCT03055013) trial to achieve the following aims: Aim 1. To identify tissue-based biomarkers that can predict benefit from neoadj/adj anti-PD-1 therapy in localized RCC. We plan to analyze baseline (untreated) tissue samples to develop biomarkers, including somatic genetic alterations and immune markers, that predict benefit from neoadjuvant/adjuvant nivolumab therapy relative to observation. Aim 2. To identify circulating plasma biomarkers that can predict benefit from neoadj/adj anti-PD-1 therapy in localized RCC. We plan to analyze baseline (untreated) plasma samples to develop non-invasive biomarkers, including circulating levels of kidney injury molecule-1 (KIM-1) and chemokines/cytokines, that predict benefit from neoadjuvant/adjuvant nivolumab therapy relative to observation. Aim 3. To evaluate the immunomodulatory effects of neoadjuvant anti-PD-1 therapy in localized RCC. We plan to test the hypothesis that neoadjuvant nivolumab leads to a reinvigorated anti-tumor immune response that correlates with improved outcomes following neoadjuvant/adjuvant nivolumab therapy. We plan to further conduct exploratory analyses aimed at (i) identifying determinants of resistance to nivolumab therapy, and (ii) characterizing putative tumor-specific T cells clones in relation to nivolumab therapy. Overall, this project is likely to generate clinically meaningful results that have the potential to improve the outcomes of patients with localized RCC who are at high risk of recurrence and death. Project Number: 1R01CA308071-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: SABINA SIGNORETTI (+2 co-PIs) | Institution: BRIGHAM AND WOMEN'S HOSPITAL, BOSTON, MA | Award Amount: $740,020 | Activity Code: R01 | Study Section: Clinical Oncology Study Section[CONC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11277056