Using Oral Delivery of Listeria-Based Cancer Vaccines to Target Gastrointestinal Cancers
Abstract
Gastrointestinal cancers, including colorectal, small intestine, and pancreatic cancers, are among the most commonly diagnosed cancers in the US. Colorectal cancer is the fourth most common cancer and the second leading cause of cancer death, while pancreatic cancer has one of the lowest 5-year survival rates and is the third leading cause of cancer deaths. While the role of the immune system in tumor surveillance and eradication has long been recognized, traditional cancer treatments have mostly focused on therapies that act directly on the tumor cells. These traditional treatments have not been very successful for treating gastrointestinal cancers. Thus, there is an urgent need to develop new therapies to treat gastrointestinal cancers. The last two decades have seen substantial growth in the understanding of the immune systems role in tumor elimination. More importantly, this understanding has led to new approaches to induce strong anti-tumor immune responses in cancer patients. One way that anti-tumor immunity is generated in patients is through administration of cancer vaccines. These vaccines may improve patient outcomes by inducing inflammation in the tumor. Ideally, they would also induce beneficial and long-lasting immune responses that can efficiently kill current tumor cells while preventing the reemergence of new ones. While several types of cancer vaccines are currently in development and clinical trials, live bacterial vaccine platforms have the unique ability to induce potent antitumor immune responses while also promoting acute inflammation that can shape the tumor landscape and promote tumor elimination. In these regards, the use of intravenous administered Listeria-based cancer vaccines has seen substantial progress recently. Oral Listeria immunization of mice was not very feasible for examining immune responses until recently. As such, very little evidence existed to support examining oral Listeria vaccines, and the relevance to humans was questionable. My lab was the first to examine T cell responses to a mouse-adapted Listeria that mimicked oral vaccination of potential Listeria vaccines in people. Recent studies from my lab with this system have demonstrated that oral Listeria immunization of mice induces superior immune responses in intestinal tissues that accumulated faster and with greater magnitude than intravenous Listeria immunization. Moreover, the immune cells induced after oral Listeria vaccines offered enhanced effector functions that could lead to better clinical outcomes. These studies examined immune responses and protective immunity with a fully virulent Listeria. Thus, this proposal will test the hypothesis that oral immunization with a Listeria-based cancer vaccine provides superior protection against gastrointestinal cancers. We will test this by examining several current highly attenuated Listeria vaccines given orally to determine how effective this approach is at inducing immune responses and combating gastrointestinal cancer. We will also determine the immune cells responsible for protection, which will inform future therapies. This proposal will determine whether oral immunization with attenuated Listeria is an effective strategy for clinical use to specifically target cancers of the gastrointestinal tract. If this study demonstrates that orally administered Listeria-based cancer vaccines are safe, immunogenic, and effective, then new clinical trials could be quickly adapted based on the cancer of the patient. We believe our proposed work will likely move the field of tumor immunology and cancer vaccines into new directions that may not have been realized previously. We believe that utilizing our extensive experience in investigating how T cells function during oral Listeria infections and applying this knowledge towards devising new ways to fight the serious illness of gastrointestinal cancers will advance this field into new uncharted territories. R
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810217
Entities
People
- Brian Sheridan
Organizations
- Stony Brook University
- United States Army