Summary of the Central Problem To Be Addressed

An exciting new type of treatment called chimeric antigen receptor therapy (CAR-T) has revolutionized our approaches to treat cancer. However, the effectiveness of CAR-T cells has been limited to blood cancers. In ovarian cancer, one initial study found that CAR-T cells that target a protein called the alpha folate receptor (aFR) is safe but no patients on the trial showed meaningful clinical responses. Although there are other CAR-T trials currently underway, there is a growing appreciation that solid tumors such as ovarian cancer can change the metabolic circuits of immune cells and cause them to become non-functional which will ultimately curb the success of CAR-T treatment. Another major hurdle is that patients need to undergo a complicated procedure termed lymphodepletion prior to receiving CAR-T treatment. This creates two constraints. First, billions of CAR-T cells need to be manufactured in the laboratory and, second, lymphodepletion plus CAR-T infusion can result in life-threatening cytokine release syndrome. Thus, this proposal will address some of these problems associated with CAR-T in ovarian cancer by (a) identifying key metabolic nodes that can be genetically engineered to improve anti-tumor immunity, and (b) genetically engineering CAR-T cells to overcome metabolic suppression. As a future goal, our work will help establish new ways to avoid lymphodepletion and mitigate adverse reactions such as cytokine release syndrome.

Relevance to the OCRP

This patient-centered translational research project addresses two focus areas: immunotherapy and host-tumor interactions. In particular, the work will be conducted using primary ovarian cancer patient specimens and utilizing tools that are being developed and compliant for use in human clinical trials. Our goal is to move the results of this project towards a direct pathway for implementation in Phase 1 trials using the infrastructure and resources in British Columbia and with our partners. By working with world class experts at the University of Pennsylvania, we want to ensure that we are deploying the results of our work in the broadest possible way.

How Is This Project Innovative?

Our study has three innovative aspects and is possible only at our centre: (1) Our unique resource of matched ovarian cancer specimens suitable for immunological studies, (2) The first examination of metabolites in ovarian cancer patient T cells, and (3) Our unique approach of combining gene-editing technology and metabolomics to improve CAR-T cell therapy.

What Is the Impact If the Project Is Successful?

Gene-editing technology and immunotherapy are arguably the most exciting areas in biomedical research. The application of metabolism at the interface these technologies will result in a significant and fundamental change in our understanding of the interaction between the immune system and cancer. The success of this proposal will have significant implications on future trials using CAR-T cells not only in ovarian cancer but beyond.