Immune checkpoint inhibitors (ICI) have the potential to cure patients with metastatic kidney cancer. There is a large difference in outcome between those that respond as compared to those that do not, who are unfortunately the majority. Therefore, we focused on patients that did not experience the full benefit of anti-tumor immune response from ICIs as 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 naturally occurs. To unleash the full potential of the immune system, we propose to ...

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Immune checkpoint inhibitors (ICI) have the potential to cure patients with metastatic kidney cancer. There is a large difference in outcome between those that respond as compared to those that do not, who are unfortunately the majority. Therefore, we focused on patients that did not experience the full benefit of anti-tumor immune response from ICIs as 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 naturally occurs. 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 (SAbR)) and promoting inflammation (with a novel drug that we discovered). Pioneering research at UT Southwestern (UTSW) identified a novel innate immune-sensing pathway, the STING pathway, leading to the Breakthrough Prize in 2019 and the development of IMSA101, a novel stimulator of the innate pathway. A phase 1 trial of IMSA101 at UTSW and elsewhere showed that IMSA101 is safe and active. Herein, we propose a novel clinical trial to evaluate the impact of SAbR given in a vaccination schedule together with IMSA101 added to the standard-of-care ICI to harness the full potential of the immune system. To accomplish this goal, we will conduct a randomized phase 2 trial. We will explore the impact of the intervention through next generation assays involving not only sophisticated tissue analyses, but also an innovative immune-PET, and will assess also determinants of sensitivity and resistance. If successful, this study will unleash the potential of the immune system through simultaneous activation of the innate and adaptive arms of the immune system in a patient population with modest benefit from ICI and which represents an unmet medical need.

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