Few procedures are available for physicians to rapidly and reliably harness immune responses to fight cancer. For example, bioinformatics tools can predict cancer proteins that T cells could react with, but vaccines developed from them commonly fail because the immunized patients do not have enough T cells that are inherently able to recognize the predicted antigens.
The goal of our research is to develop injectable nanoreagents that can genetically program T cell receptors (TCRs) into circulating lymphocytes, enabling them to recognize cancer proteins. Specifically, we hypothesize that customized cancer-targeting can be introduced into immune cells by combining anti-cancer vaccines with techniques that induce endogenous CD8 T cells to express TCRs specific for the vaccines, and consequently provide them with the ability to react with cancer cells. We further hypothesize that this platform can be used to program helper cells with defined “MHC class-II-restricted TCRs”, and thereby improve responses to tumor antigens compared to conventional immunization methods.
Our multidisciplinary team of immunologists, bioengineers and geneticists has already established that injected nanoparticles can deliver engineered TCR genes into host T cells in a way that, once they are stimulated by vaccines, the lymphocytes recognize cancer antigens. Following rapid vaccine-induced expansion, these programmed cells continue to differentiate into long-lived memory T lymphocytes.
We propose to develop a suite of nanoparticle reagents that can rapidly establish anti-cancer immunity by programming in situ specific receptors into the patient’s T cell pool. To achieve this, we will pursue the following Specific Aims:
(1) to improve our efficiency for introducing vaccine specificity into circulating CD8+ T cells; (2) to establish that this approach boosts immune responses; and (3) to determine if our methods promote the regression of cancer regardless of the patient’s pre-existing TCR landscape.
To assure the medical relevance of our findings, we will (i) program the lymphocytes to express an affinity-optimized receptor specific for the tumor antigen mesothelin, and (ii) use them to treat a genetically engineered mouse model that faithfully recapitulates human pancreatic ductal adenocarcinoma from inception to invasion.
We believe that the data, reagents, and application methods generated by our research will provide the basis for a broad repertoire of gene modification systems that can generate selective immunity against cancer and other diseases.
