Sarcoma Immunotherapy by Attenuated Salmonella Typhimurium Engineered for Tumor Specific Production of Immunomodulators.
A significant impediment to the development of curative cancer therapy is the dose-limiting toxicity of therapeutic anticancer treatments. We have developed tumor-targeted bacterially delivered anticancer immunotherapy to overcome this obstacle and are working to optimize nontoxic systemic delivery of multiple immune modulating proteins to tumors. Our laboratory has successfully translated our first generation of bacterial based cancer therapy that only produces one immune modulating protein with a license agreement with a pharmaceutical company and a current Phase 2 trial for Saltikva (Salmonella-IL2) in patients with stage 4 metastatic pancreatic cancer (NCT04589234). We are now focused on the development of our NEXT GENERATION of bacterial based cancer therapy that will deliver multiple immune modulating proteins. This therapy has been successfully tested in a genetically engineered mouse model of autochthonous breast cancer, but not in a sarcoma model. Thus, treating mice burdened with a chemically induced sarcoma will allow the full potential of our novel anticancer therapy to be demonstrated in both primary and metastatic tumors. The experiments in this proposal will provide data needed to initiate clinical trials of this therapy in human volunteers with solid tumors including both primary and metastatic sarcomas. The hypothesis to be tested is that systemic administration of a virulence-attenuated strain of Salmonella Typhimurium, engineered for tumor-specific secretion of immunomodulatory proteins, will eradicate chemically induced fibrosarcoma, without the toxicity that precludes curative dosing of current anticancer therapy. The following two specific aims are proposed: Specific Aim 1: The anticancer efficacy of an optimal combination of immune modulating proteins, secreted into tumors from genetically engineered bacteria, will be determined in a mouse model of autochthonous metastatic fibrosarcoma. Strains of S. Typhimurium engineered for immunogenic stealth and tumor specific secretion of immunodulators will be administered to mice with chemically induced sarcoma. Animals will be monitored for diminished tumor growth and an expected increase in survival. Specific Aim 2: The mechanism underlying the efficacy of this bacterially delivered cancer immunotherapy will be elucidated. Multiplex cytokine/chemokine protein analysis and single-cell RNA sequencing will identify changes in the tumor microenvironment immune contexture following administration of this therapy and inform the choice of immunomodulators to be engineered into bacteria for human clinical trials. As time permits, Salmonella strains engineered to secrete various combinations of immunomodulators will be tested for efficacy and effects on the function of the immune system within tumors. The optimal bacterial cancer therapy strain identified during this work will be included in applications to the FDA for human clinical trials in sarcomas and other solid tumor cancers.