Targeting Interleukin-1beta to Overcome Adaptive Immune Resistance in Renal Cell Carcinoma

Rationale: Despite a significant risk of disease recurrence, systemic therapy prior to surgery (neoadjuvant therapy) has no role in patients with kidney cancer. Therefore, new treatments that eliminate tumor cells early and prevent disease recurrence are critical to improving patient outcomes. Immunotherapy, which is effective in metastatic kidney cancer, is an attractive approach in the neoadjuvant setting given that treatments that activate the immune system against tumors have revolutionized cancer therapy with long-lasting responses and the possibility of cure for some patients. Although immunotherapy is effective for many patients with kidney cancer, there is still a significant number of patients who do not respond to treatment. Kidney tumors have multiple ways to hide from the immune system. We recently discovered that a chemical messenger called Interleukin-1beta (IL1ß) is an important signal that kidney tumors send to help escape immune destruction. Second, we found that blocking IL1ß can enhance the immune response against tumors by preventing immunosuppressive cells (suppressive macrophages) from accumulating into tumors. Based on these discoveries, we are testing in an ongoing clinical trial, whether an inhibitor of the well-known immune target PD-1 (spartalizumab) combined with a drug that blocks IL1ß (canakinumab) can activate the immune system against kidney tumors and lead to long-term off-treatment responses. As part of this trial, we are collecting significant amounts of fresh tumor tissue, which will allow us a unique opportunity to understand how the therapy works and which patients are most likely to respond. In addition, we plan to use the information gathered from these biological studies to identify new targets/treatments that will be tested in mice and 3D tissue culture (organoids) that more accurately reflect tumor biology. We anticipate that these studies will accelerate the development of rationally designed future clinical trials. To do this, we have assembled an experienced team of leaders in the fields of pathology, immunology, computational biology, and clinical trial design with expertise in cutting-edge methods that can determine how therapy changes both the local tumor immune system and the overall immune system. The specimens we are collecting could also reveal previously unknown aspects of kidney cancer biology, which could be used to develop a next-generation of targeted immunotherapy studies aimed at improving outcomes for patients with kidney cancer. Given our strong track record in drug development and our rapidly accruing trial, we will be able to efficiently apply our findings to future studies that incorporate specific patient-related outcomes. If successful, this treatment could offer the potential for long-term remissions. Applicability: Taken together, this work could form the basis for larger future clinical trials and lead to a new treatment strategy for kidney cancer. Patients diagnosed with localized kidney cancer would still be treated with surgery as a potentially curative primary treatment. However, they would also receive a new immunotherapy regimen of anti-PD-1 plus anti-IL1ß therapy prior to surgery. We are hopeful that this combination will allow the immune system to destroy and develop memory against the cell population that leads to cancer progression. If this kind of treatment is effective, it could mean that patients with kidney cancer could live without progression. Furthermore, by identifying mechanisms of resistance to therapy, we will be able to use new computational tools to identify drugs that can overcome lack of response to immunotherapy. We will then test these drugs in unique model systems in the laboratory. If successful, these experiments could form the basis for future clinical trials and accelerate development of new treatments for kidney cancer.