Immune therapies have significantly improved outcomes for cancer patients with poor prognosis in recent years, in many cases providing complete remissions with no trace of residual disease. However, these therapies are currently restricted to specific cancer types, and do not reach the majority of cancer patients. The two most successful forms consist of either using blocking antibodies specific for inhibitory ligands commonly expressed on T lymphocytes, allowing enhanced functionality of T cells, known as inhibitory checkpoint blockade (ICB), or the engineering of autologous T cells to target tumors through chimeric antigen receptors (CARs). Unfortunately, CAR T cell therapy has shown limited efficacy in solid tumors, and ICB is most effective in tumors with pre-existing immune infiltrate and heavy mutational loads. Thus, significant innovation is needed to extend the benefits of immune therapies to the majority of cancer patients. Our lab has recently identified the structured RNA 7SL1 (RN7SL1) as capable of stimulating immune response genes in tumor cells following secretion of the RNA by stromal cells. Although the 7SL1 RNA is not well studied in an immune context, structured RNA is a well-known immunostimulatory motif. Thus, I hypothesize that unshielded 7SL1 in the tumor microenvironment stimulates immune activation and contributes to ICB responsiveness. Given that CAR T cell therapy has not been effective in solid tumors, engaging an endogenous immune response similar to that seen following administration of ICB, which has shown efficacy in solid tumors, is an attractive prospect. To that end I have designed a T cell-based system for delivering structured RNA directly to the tumor microenvironment. I hypothesize that combining the production of stimulatory RNA with CAR T cell functionality in the tumor microenvironment will stimulate endogenous immune responses and improve the anti-tumor efficacy of CAR T cells in solid tumors. In order to test these hypotheses, I will use fibroblast cell lines designed to secrete high or low levels of unshielded 7SL1 in the tumor microenvironment in combination with current ICB regimens to determine the contribution of this stimulatory element to antitumor immunity. Additionally, I will assay the efficacy of this newly developed T cell system using syngeneic tumor models expressing a model antigen. These approaches will be complimented by genetic knock-out mouse models to determine the importance of specific immune cell types in carrying out these anti-tumor responses. In total, these experiments will serve to determine the importance of a novel immunostimulatory RNA to anti-tumor immunity and test the functionality of a novel CAR T cell-based approach to anti-tumor immune activation.
Immunotherapy has been a transformative approach to the treatment of cancer that produces remarkable outcomes in a subset of patients by engaging the host immune system to recognize and eliminate malignant cells. However, the benefits of these therapies are limited to small pools of patients with specific types of cancer that are predisposed to immune recognition. This proposal seeks to understand how innate immune cues in the tumor microenvironment influence immune recognition of malignant cells, and to use this information for the rational design of next generation cellular immune therapies in order to extend benefits of immunotherapy to a wider range of patients with poor prognosis.
