As our understanding of the immune system increases, so do our expectations of one day being able to harness the power and specificity of the immune system and direct it towards the treatment or prevention of malignancies. To date, only a few limited successes have been achieved, but, with the development of newer agents and an improved ability to monitor the immune response, we now see the emergence of an exciting, revitalized field of cancer immunotherapy. The applicant's focus has been on the development of CEA-based vaccines. CEA is expressed on many common malignancies; therefore vaccines targeting CEA would have extremely broad clinical utility and a dramatic impact on the survival of a large population of patients. In the past two years, the applicant has performed two clinical trials of CEA-based vaccines which have proven these compounds to be safe and capable of generating new T cell reactivity which is further increased by the addition of GM-CSF (and possibly IL-2). Most importantly, the applicant is accumulating evidence of clinical activity in patients with cancer including prolonged cancer regressions. New evidence strongly suggests that the addition of costimulatory molecules (B7-1, ICAM-1, LFA-3) to the vaccine constructs and modifications to the CEA gene itself (6D mutation) results in dramatic improvements in the pre-clinical activity of these compounds. The goal of this project is to rapidly develop these new vaccine constructs through a series of efficient clinical trials which are designed with traditional phase I and II endpoints and to allow for comparisons of immunologic endpoints between the different treatments. In the end, the applicant will have determined the optimum vaccine dose and schedule, confirmed the role of cytokines on the immunologic endpoints, and determined the independent impact of the 6D epitope and chemotherapy on the immunologic response in patients. The important translational aspect of these trials will be the development and validation of a novel intermediate endpoint, the quantification of circulating CEA positive cells in patients, and the relationship between this, the immune response, and clinical response. So far, the applicant's experience with the first generation CEA-based vaccines has generated a great deal of excitement, and yet he anticipates even more from the newer vaccine constructs.
| Hampton, Regina; Walker, Mignon; Marshall, John et al. (2002) Differential expression of carcinoembryonic antigen (CEA) splice variants in whole blood of colon cancer patients and healthy volunteers: implication for the detection of circulating colon cancer cells. Oncogene 21:7817-23 |
