Multimodal microbe-mediated therapies for synergistic treatment of triple negative breast cancer

The National Cancer Institute awarded the University of Massachusetts $2.736 million on September 1, 2026, under the Cancer Treatment Research program (CFDA 93.395) to develop multimodal microbial therapies for treating triple negative breast cancer resistant to immune checkpoint inhibitors.

The award funds research to engineer microbial therapies that deliver therapeutics into cancer cells, deploy oncolytic viruses, and target radiation to tumors, with the goal of generating durable antitumor responses in immunotherapy-resistant disease. The program integrates expertise across the University of Massachusetts Amherst and Weill Cornell Medicine in tumor biology, drug delivery, immune oncology, synthetic biology, and radiology. Work is organized into three projects: Project 1 addresses immune suppression through intracellular delivery of the SARS-CoV-2 spike antigen and CRISPR-controlled Salmonella effectors; Project 2 targets tumor heterogeneity by delivering oncolytic viruses; and Project 3 develops a theranostic approach using bacteria-targeted radiohaptens. Two shared resource cores provide synthetic biology tools for vector construction and strain optimization. Performance takes place in Hadley, Massachusetts with a period of performance running through August 31, 2031.

Abstract

Overall the goal of the proposed research is to develop microbial therapies that generate durable antitumor responses. Most breast cancer subtypes, particularly triple negative breast cancer (TNBC), respond poorly to immune checkpoint inhibitors (ICI), which makes developing treatments for ICI-resistant tumors a critical unmet medical need. Our program will engineer microbial therapies that release therapeutics into cancer cells, deliver oncolytic viruses, and target radiation precisely to tumors. Understanding the biological mechanisms that control how these therapies interact with tumor tissue and the immune system is essential for their clinical translation. The program was designed to integrate complementary expertise in tumor biology, drug delivery, immune oncology, synthetic biology, and radiology across umass amherst and weill cornell medicine. IT has three main aims: (aim 1) develop microbial therapies to treat ICI-resistant TNBC; (aim 2) determine the biological mechanisms of microbial immune induction; and (aim 3) develop a suite of clinically relevant multimodal bacterial therapies. Through these aims, the proposed program project will create versatile treatments to overcome ICI resistance in TNBC and address key barriers to the clinical adoption of microbial therapies. The program has three projects, each designed to address distinct mechanisms of immune resistance in breast cancer: project 1 aims to overcome immune suppression by intracellular delivery of the sars-COV-2 spike antigen and crispr-controlled salmonella effectors; project 2 targets tumor heterogeneity by delivering oncolytic viruses; and project 3 focuses on developing a theranostic approach for TNBC using bacteria-targeted radiohaptens. These projects are supported by two shared resource cores: core 1 will develop synthetic biology tools for vector construction and strain optimization; and core 2 will provide immunological analysis tools and clinically relevant animal models. Animal models are necessary because the complex interactions among live bacterial vectors, tumor tissue, and the immune system cannot be recapitulated in vitro. Immunocompetent TNBC mouse models provide the physiological complexity needed to evaluate safety and antitumor efficacy prior to clinical translation. The projects each generate a distinct therapeutic modality and are synergistically integrated to create multimodal bacterial therapies that target multiple immune resistance pathways. The foundations of the proposed research are well established. In preliminary studies, we have (1) developed a strain of salmonella capable of delivering proteins into cancer cells; (2) engineered salmonella to deliver oncolytic viruses into cancer cells and bind radiotherapeutic agents; (3) demonstrated that intracellular delivery of exogenous antigens can clear immunologically cold tumors and establish durable anticancer immunity. Microbial therapy could benefit a broad range of breast cancer patients, particularly those with TNBC and in rural communities with ICI-resistant, immunosuppressive cancer types. If successful, this research will yield potent, safe, and 'off-the-shelf' microbial therapies that require no patient-specific customization.