Abstract

Reshaping immunotherapy landscape.

Cancer thrives by preventing the immune system from targeting tumor cells. While current immunotherapies use dendritic cells to activate T-cells towards specific tumor antigens, they remain expensive and of variable efficiency against tumor immunosuppressive environment. To develop personalized therapies, our team focused on engineering yeast Saccharomyces cerevisiae for targeted immunotherapy. First, we developed a software to select the best tumor antigen from patient sequencing data. Second, we created a yeast chassis to prime the immune system with the targeted antigen. This chassis was tested successfully in vitro on mouse tumor cells and in vivo on mice presenting melanoma. Three complementary strategies were combined to improve the chassis efficiency. First, in order to modulate the tumor environment, yeast secreting the specific immune modulator IFNgamma was encapsulated into alginate beads to be injected in tumors. Secondly, to break the immune tolerance against cancer cells, T4 and T8 lymphocytes were elicited by a yeast antigen display system that can be adapted to any tumor antigen for personalized therapy. Last, to deliver cytotoxic compounds solely in the tumor environment, a yeast hypoxia bio-sensor was designed. A side project consisted in engineering Escherichia coli to drive MAIT lymphocytes against cancer cells instead of their original targets, parasitized cells. Our standardized and customizable chassis takes advantage of these approaches to make personalized medicine a reality, with a scalable cancer therapy.