Project Summary Immune checkpoint inhibitors (ICI) have the potential to cure patients with metastatic renal cell carcinoma (RCC). For those experiencing a complete response (CR), induction Ipilimumab (Ipi)/ Nivolumab (Nivo) followed by maintenance Nivo results in overall survival (OS) rates of 97% at 4 years. However, CR rates occur in ~10% of patients. Survival rates plummet in patients with progressive disease (PD) and even stable disease (SD). Despite Nivo maintenance, patients with SD after induction (36%) show significantly reduced 4-year OS rates (55% vs 97%). While by comparison to PD patients (OS rates ~20%), patients with SD derive some benefit from ICI, the full potential of immunotherapy is not realized. We hypothesize that the addition of complementary immune strategies will increase responses and eventually cure rates for patients with SD after induction. This represents an unmet medical need. Most immunotherapy approaches to date have focused on amplifying an adaptive immune response (i.e., ICI), but more effective strategies may result from simultaneously activating the innate and adaptive immune arms as it normally occurs physiologically. To unleash the full potential of the immune system, we propose to induce innate immunity by stimulating antigen presentation (through immunogenic cell death triggered by stereotactic radiation) and promoting inflammation (with a novel STING agonist we discovered). Pioneering research at UT Southwestern Medical Center (UTSW) identified a novel innate immune- sensing pathway, the cGAS-cGAMP-STING pathway, leading to the Breakthrough Prize in Life Sciences in 2019 and the development of IMSA101, a novel STING agonist. A phase 1 trial of IMSA101 (NCT04020185) at UTSW and elsewhere showed that IMSA101 is safe and active. Herein, we propose a novel adaptive clinical trial to evaluate the impact of stereotactic ablative radiation (SAbR)/ IMSA101 added to standard-of-care (SOC) Nivo maintenance in patients with SD following induction Ipi/Nivo to harness the full potential of the immune system. To accomplish this goal, we will conduct a randomized phase 2 trial comparing this regimen to SOC maintenance Nivo. The study is powered to detect a clinically meaningful difference in response rates from 5% to 35%, which can be accomplished with 50 patients. We will explore the impact of the intervention through pharmacodynamic studies involving not only sophisticated tissue analyses, but also an innovative PD-L1 PET. We are uniquely positioned to carry out these studies given: (i) the discovery of the cGAS-cGAMP-STING pathway and development of IMSA101; (ii) our pioneering development of SAbR applications for RCC with possibly the largest SAbR RCC program globally; (iii) our prior success executing clinical trials combining SAbR with ICI in RCC patients; and (iv) our pioneering work leveraging PD-L1 PET in renal cancer. If successful, this study will harness the full potential of the immune system through simult...