Occult Colorectal Cancer Elimination by GUCY2C-Directed Immunotherapy
Abstract
Topic and Military Health Focus Areas: This project directly addresses the Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of colorectal cancer (CRC) and metastatic cancer and, indirectly stomach cancer and esophageal cancer, and the FY21 PRCRP Military Health Focus Area gaps in cancer prevention, early detection/diagnosis, prognosis, and/or treatment that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public. Objectives and Rationale: For many CRC patients, a combination of surgery and chemotherapy is intended to be curative, however, CRC returns (recurs) in the form of metastatic disease in many patients (approximately 10% for stage I, approximately 20% for stage II, and approximately 35% for stage III). CRC recurrence occurs from a small number of undetectable cancer cells that were not removed in the surgery or killed by the chemotherapy – this is known as minimal residual disease (MRD). Therefore, safe and effective new therapies are needed to fully clear MRD in many CRC patients. Therapies that target the immune system (immunotherapy) have emerged in the last decade as a new form of cancer therapy unique from surgery, chemotherapy, and radiation therapy. However, immunotherapy is available, and only modestly effective, for only a small portion (approximately 15%) of CRC patients who have a particular subtype of advanced CRC. Effective immunotherapeutics for the majority of CRC patients are lacking. In this context, we identified a molecule on the surface of all CRC cells, known as GUCY2C, that could be a perfect target for immunotherapies. We created vaccines that could be given to CRC patients after they receive standard surgery and chemotherapy that could elicit an immune response that finds and kills residual CRC cells (MRD). In animal models, that vaccine strategy was safe and highly effective in models of MRD. Thus, we hypothesis that GUCY2C-directed vaccination safely induces immune responses and MRD clearance in CRC patients. Here, we propose a phase 1 clinical trial of GUCY2C-directed vaccination in CRC patients with MRD to test its (1) safety and (2) ability to induce GUCY2C-specific immune responses and induce MRD clearance. Impact: In the short-term, these studies will establish the necessary safety and preliminary efficacy data for continued clinical testing of this vaccine strategy. Success here will lead to expanded phase 2 studies in not only CRC, but also stomach and esophageal cancer, patients – GUCY2C is found in many stomach and esophageal cancers, too. Continued development is expected to lead to phase 3 trials testing its ability to prevent metastatic recurrence and improve patient survival, leading to its Food and Drug Administration approval. If successful, the new therapy identified in this proposal could have a significant long-term impact by reducing gastrointestinal (GI) cancer mortality in military and civilian populations and the costs associated with disease management to the military health care system. Indeed, the healthcare impact of this proposal can be best appreciated by considering that these GI cancers (colorectal, stomach, and esophageal) account for 12% of all cancer-related deaths in civilian and military populations (more than 75,000 U.S. deaths annually). Overarching Challenge: Immunotherapies directed at new targets that can be safely applied to all CRC patient populations at risk of recurrence would remarkably impact CRC care. In the context of high toxicity and low efficacy with established immunotherapies in this disease, robust immunization strategies targeting novel targets, such as GUCY2C, may provide safe and effective immunotherapy for prevention of recurrent metastatic disease in patients with MRD who are ineligible to receive other immunotherapies. Thus, this proposal addresses all aspects of the FY21 PRCRP Overarching Challenge to transform
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210207
Entities
People
- Adam E. Snook
Organizations
- Thomas Jefferson University
- United States Army