Towards therapeutic vaccines for colorectal carcinoma: a review of clinical trials
ABSTRACT
Colorectal carcinoma is a leading cause of cancer-related mortality. Despite the introduction of new cytotoxic drugs, improved surgical and radiotherapeutic techniques, a large proportion of colorectal carcinomas remain incurable. New targeted therapeutic strategies, including immunotherapy, are being explored as complementary treatments. Recent advances in immunology and molecular biology have opened new avenues for the clinical testing of rationally designed vaccination strategies against cancer. The present report reviews the results of therapeutic vaccine trials in colorectal carcinoma, published mainly in the past 6 years. Tumor-associated antigens (self-antigens) have been targeted by therapeutic vaccination in more than 2000 colorectal carcinoma patients. The results demonstrate that tumor antigen-specific immune responses are reproducibly induced; that is, tolerance can be reversed, without the induction of serious adverse events or autoimmune disorders. No long-term autoimmune side effects have been observed after a minimum follow-up of 4 years in over 700 patients. Over 1300 colorectal carcinoma patients with minimal residual disease have been enrolled in randomized controlled Phase II/III trials using autologous tumor cell vaccines. A significantly improved overall survival was noted for Stages I-IV colorectal carcinoma patients utilizing Newcastle-disease virus as an adjuvant. Autologous tumor cells mixed with bacillus Calmette-Guerin (BCG) were of significant clinical benefit for patients with Stage II colon cancer. Results of randomized controlled trials targeting Ep-CAM have shown clinical benefit in subgroups of patients. Several new generation vaccines have demonstrated excellent safety profile and immunogenicity. Some studies have also demonstrated a statistically significant correlation between the induced immune response and prolonged overall survival, which should be confirmed in enlarged trials. Although it is unlikely that active specific immunotherapy will provide a standard complementary therapeutic approach for colorectal carcinoma in the near future, the results so far are encouraging. Randomized controlled vaccine trials targeting molecularly defined tumor antigens are warranted, particularly in colon carcinoma with minimal residual disease.