Intracellular Bacterial Delivery of Vaccine Antigens to Establish T-Cell Antitumor Immunity in Triple-Negative Breast Cancer
Abstract
Background: In the proposed research, we will create a bacterial therapy to treat immune-resistant breast cancer. Most breast tumors, and especially triple-negative breast cancers (TNBCs), do not respond to immune checkpoint inhibitors (ICI). These immune therapies are effective in only about 5% of TNBC patients. TNBC is an aggressive form of breast cancer that responds poorly to conventional therapies and has a poor prognosis. Most triple-negative tumors grow quickly and rapidly spread to the bone, liver, lung, and brain. Metastatic spread is the primary cause of death from breast cancer. The average 5-year survival for TNBC is 65%, which drops to 11% once tumors have spread. Developing new therapies for TNBC and metastatic disease are critical medical needs. Overarching Challenge: The primary goal of the research is to create a bacterial immunotherapy to treat TNBC and metastatic disease. We propose to develop a therapy that refocuses vaccine memory CD8 T cells to generate antitumor immunity. We will create antigen-delivering Salmonella (ADS) to deliver the measles nucleoprotein directly into the cytoplasm of cancer cells. This antigen is a component of the measles, mumps, and rubella (MMR) vaccine, a common childhood vaccine that is administered to 91% of the U.S. population. ADS therapy utilizes new technology that we recently developed to deliver antigens specifically into cells in tumors. We have strong evidence that this strategy will work. In preliminary research, we used ADS to deliver a model antigen to mice with immunologically cold pancreatic tumors. The bacterially delivered antigen activated vaccine T cells, cleared primary tumors, and established immunity against the cancer. The core goal of the proposed research is to develop this strategy into an effective treatment for immune-resistant breast cancer. Type of Patients: ADS therapy would be effective for a broad range of breast cancer patients, especially women of African ancestry and women under 40. Women in these groups have increased mortality and a higher risk of developing TNBC. Military women, who are predominantly (>90%) under 40, have a 20%-40% increased risk of breast cancer. African American women have similarly poor survival, with mortality rates 41% higher than European Americans. Triple-negative tumors from African American women have high densities of CD8 T cells and immunosuppressive macrophages, indicating T cell exhaustion and resistance to immune clearance. By targeting memory T cells (from prior vaccination) that are less likely to become exhausted, ADS therapy would avoid these limitations. Potential Clinical Applications: In its primary application, ADS therapy would be used for patients with late-stage breast cancer. For the majority (~75%) of these patients, resected tumors have recurred, spread to secondary sites, and chemotherapy is no longer effective. Clinically, we anticipate that ADS will be administered with intravenous doses once a week, similar to preclinical animal trials. If the therapy performs as observed in animal models, it will colonize all tumor masses in a patient, deliver the measles antigen into cancer cells, and educate the immune system to the tumor’s neoantigen signature. This immune induction would eliminate all existing lesions and prevent new ones from forming. A secondary preventative strategy could impact a greater number of patients. In this strategy, ADS would be administered prior to excision of the primary tumor to promote colonization and identification of tumor neoantigens. Generating antitumor immunity before surgery would have a prophylactic effect, reducing the incidence of both recurrence and metastatic disease. Projected Time to Patient-Related Outcomes: During the 3-year research period, the proposed experiments will demonstrate the safety and efficacy of using ADS to treat breast cancer. Results from these experiments will be the basis for Investigational New Drug (IND)-enabling
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310067
Entities
People
- Neil S Forbes
Organizations
- United States Army
- University of Massachusetts Amherst