We are exploring therapeutic vaccines as immunotherapy for metastatic cancer. We've created vaccines containing guanylyl cyclase C (GUCY2C), an antigen expressed in normal intestinal epithelium and all primary and metastatic human colorectal cancer (CRC) specimens. Immunization elicited CD8⁺ T, but not CD4⁺ T or B, cell responses in multiple strains of mice. Moreover, responses effectively prevented the development of CRC metastases in lung and liver and treated established CRC metastases in the lungs. This occurred in the absence of autoimmunity against normal GUCY2C-expressing tissues. Currently, we are collaborating with a large multi-disciplinary team of investigators, including laboratory-based scientists, medical and surgical oncologists, pathologists, statisticians, and clinical trial professionals to test GUYC2C vaccines in gastric, esophageal, pancreatic, and colon cancer patients, with the hope that this vaccine can improve the survival of patients with these cancers.
GUCY2C Vaccine Efficacy
PET images of mice with metastatic colorectal cancer in the lungs immunized with control (left) or GUCY2C vaccine (right).
Self tolerance limits immune responses to self-proteins, preventing autoimmunity and creating a significant barrier to developing cancer immunotherapeutics. Preclinical and clinical studies have revealed a novel tolerance mechanism limiting GUCY2C-specific immune responses and antitumor efficacy. Rather than eliminating all three adaptive immune lineages (CD4⁺ T, CD8⁺ T, and B lymphocytes), GUCY2C tolerance was characterized by selective CD4⁺ T cell tolerance, while CD8⁺ T and B cells were unaffected. Importantly, CD4⁺ T cells serve a critical "helper" role in immune responses, and in the absence of GUCY2C-specific CD4⁺ T cell responses, CD8⁺ T and B cell response were also inhibited. Further defining mechanism(s) underlying select CD4⁺ T cell tolerance to GUCY2C will create strategies for next-generation GUCY2C vaccines.
Adoptive T-Cell Therapy
Development of innovative paradigms beyond vaccines is needed to safely and effectively treat patients with advanced, bulky tumor metastases. While a vaccine relies on a patient's immune system to create an antigen-specific immune response, adoptive cell therapy (ACT) using engineered T cells offers unique advantages. Specifically, tolerance removes antigen-specific T cells during their maturation, limiting the number and the potency of T cells that escape tolerance and can be harnessed by vaccination. In contrast, T cells can be engineered and expanded ex vivo to produce large numbers of cells expressing receptors of high affinity, maximizing their potency. Importantly, we have shown that while GUCY2C vaccines possess antitumor activity, they are limited by tolerance, reducing their efficacy against large, established tumors. In mouse models, GUCY2C-targeted ACT is superior to GUCY2C-targeted vaccines in the context of established tumors. Similar techniques also have produced remarkable clinical successes in melanoma, neuroblastoma, and leukemia, but ACT approaches for adenocarcinomas remain undefined. Currently, we are interested in identifying antigen-targeted ACT approaches which can be translated to patients with metastatic disease originating in mucosal tumors. Preclinical studies have shown promising results with GUCY2C CAR-T cell therapy and we are working towards clinical trials with this approach.