Targeting Immunosuppressive Adenosine to Enhance Vaccinia Virus Renal Cancer Oncolysis
Abstract
Rationale and Scientific Objective: Renal Cell Carcinoma (RCC) is expected to affect 79,000 Americans in the and cause about 14,000 deaths in 2022. While RCC can be cured in most cases by surgery when diagnosed and treated early, renal cell cancer recurs in about half of those patients. Due to its aggressive nature, spread to vital organs, and the resistant nature of the cancer, RCC is a fatal disease when advanced. While significant advances have been made in the understanding the biological basis of RCC, leading to improved treatment options (targeted therapies and immunotherapies) and survival, many patients with metastatic RCC patients eventually stop responding to treatment and succumb to their disease. Therefore, there is an urgent need to find new strategies to overcome resistance and cure renal cell cancer. Oncolytic viruses are promising anticancer therapies, designed to preferentially target and kill tumor over normal cells, and by stimulating antitumor immune responses. Unfortunately, and as with other treatments, including immunotherapies, only a small percent of patients enjoy durable, complete responses from oncolytic virus treatments. The causes of the limited efficacy to these therapies are not fully understood but may be similar to those causing resistance to immunotherapies. Among the mechanisms responsible for limited treatment efficacy, the adenosine pathway plays a critical role. Adenosine, a by-product of ATP, is produced in tumors during hypoxia (low oxygen), tissue necrosis, cell death and inflammation, and often, because of anticancer treatments. Tumor adenosine causes treatment resistance by suppressing antitumor immune responses, limiting the action of the immune cells activated by viruses and immunotherapies. Therefore, targeting the adenosine pathway is a promising strategy to overcome resistance to immune and virus therapies. Our long-term goals are to improve clinical outcomes and cure rates in advanced renal cell carcinoma by using oncolytic virus-based biotherapies. The objective of this application, which is a step toward achieving our long-term goals, is to investigate the role of, and target tumor adenosine to improve the efficacy of oncolytic viral therapies in preclinical models of renal cell carcinoma. The FY21 KCRP Focus Area to be addressed is Developing novel therapeutic strategies for the treatment of kidney cancer. To achieve our goals, we will use a novel oncolytic vaccinia virus, JX-594, which is currently being used in a clinical trial in RCC. This viral agent has shown safety in patients with RCC and early evidence of promising activity. As we will use mouse models of kidney cancer, we will use the mouse version of JX-594, to be able to mimic the effects we see in humans. Our experiments will test the hypothesis that vaccinia virus induces adenosine production in the tumors by increasing levels of CD39 and CD73, which mediate the production of adenosine, and that blocking adenosine will enhance the antitumor efficacy of the vaccinia virus based immuno-virotherapies. Applicability of the research: Positive results from our research will advance the fields of oncolytic virotherapy and renal cell cancer, as they will validate the adenosine pathway as a target to improve oncolytic virus efficacy and clinical outcomes in RCC. Our studies can be applied to both clear cell and non-clear cell renal cell carcinoma patients because the virus has potent activity in both RCC subtypes (demonstrated in preliminary data). They will generate the knowledge necessary for future studies investigating the effects of alternative viral vectors on the adenosine pathway and novel adenosine targeting strategies beyond those proposed by us. Moreover, our preclinical studies will provide a strong rationale for future clinical trials (in the next 2 to 3 years) in patients with metastatic RCC who have failed currently approved therapies. We envision that in the long term,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310839
Entities
People
- Jaime Merchan
Organizations
- United States Army
- University of Miami