Therapeutic Vaccines for Colorectal Cancer

Abstract

A number of cancer vaccine strategies for the treatment of colorectal cancer have entered clinical trials. Whole tumor cell vaccines have been developed from both patients’ autologous tumor cells as well as established allogeneic tumor cell lines. A vaccine consisting of autologous tumor cells along with bacillus Calmette-Guerin (BCG) has shown a potential clinical benefit in patients with stage II colon cancer. Other approaches using autologous tumor cells have involved transfection of primary tumor cells with cytokine genes. Allogeneic tumor cell vaccines have also been modified to express cytokine genes. Vectors have been studied extensively as a means of vaccine strategy. One tumor-associated antigen (TAA) that has been extensively studied in viral vector vaccines is carcinoembryonic antigen (CEA). A recombinant vaccinia virus containing the CEA transgene (rV-CEA) has been shown to elicit CEA-specific immune responses in advanced carcinoma patients. However, patients receiving multiple vaccinations had limited increases in CEA-specific responses by the third vaccination. This problem may be overcome by the use of non-replicating poxviruses, which have been shown in clinical trials to be safe and to elicit CEA-specific responses. However, recent clinical studies have shown that the optimal use of poxviruses is to prime with vaccinia, followed by boosts with avipox vectors. A recent randomized clinical trial showed that patients primed with rV-CEA and boosted with avipox-CEA had greater immune responses compared with patients receiving three 1-monthly avipox-CEA vaccinations followed by an rV-CEA vaccination. Furthermore, a statistically significant survival advantage was noted in the prime/boost arm. Ongoing studies are now incorporating the genes for costimulatory molecules along with TAA in these vectors. Another vaccine strategy involving TAA that is currently in clinical trials for colorectal cancer is the peptide vaccine. Dendritic cells (DCs) are considered to be the most potent antigen-presenting cell, thus providing an attractive modality for cancer vaccines. In addition to using DCs for peptide-based vaccines, a number of other strategies, including transfection with messenger RNA, have produced specific T-cell responses in clinical trials. In addition, several clinical trials using murine anti-idiotype antibodies as vaccines for patients with advanced colorectal cancer have shown both immunologic responses as well as clinical responses.