Tumor-Specific BCG Therapy in Colon Cancer

Abstract

The ability to achieve systemic tumor immunity by means of an intradermal BCG/autologous tumor cell vaccine (active specific immunotherapy; ASI) was a major advance in the guinea pig immunotherapy model. A series of studies have demonstrated that BCG mixed with tumor cells is effective in inducing a degree of systemic tumor immunity capable of eliminating a limited disseminated tumor burden when the vaccine is carefully contwlled for variables with respect to vaccine preparation and administration, namely: the number of tumor cells (10' optimal), the ratio of BCG organisms to tumor cells (1 : 1), maintenance of metabolidy viable tumor cells, and vaccination regimen (3 vaccines, one week apart). Further studies in the guinea pig model demonstrated the feasibility of preparing tumor cell suspensions from enzymatically dissociated solid tumors without loss of immunogenicity, a requirement for the preparation of human tumor vaccines. Furthermore, the regional lymph nodes draining the intradermal vaccination sites were found to be critical. It was possible in this model to demonstrate that neither allogeneic cells, dead cells, or cell components (antigenic extracts) were effective. It was also demonstrated that BCG components were not effective substitutes for whole, viable BCG cells. Neither autologous tumor cells or BCG alone were effective in this model. Over the past ten years, we have translated this animal model into a prospectively randomized, controlled clinical trial in patients with colorectal cancer. The objectives have been to: (i) determine whether AS1 in colorectal cancer patients could enhance the delayed cutaneous hypersensitivity (DCH) responses to autologous tumor cells, and (ii) determine whether this therapy could prolong the disease-free interval and survival of these patients. We will update this trial, including the first 76 patients. Patients underwent standard surgical resection. The mechanical and enzymatic dissociation and cryopreservation procedures for vaccine preparation will be discussed. Patients with lesions which had grown through the entire bowel wall or had spread to the regional lymph nodes were candidates for this study. Control patients received surgical resection alone or resection plus 5,040 rad of pelvic irradiation if the lesion was below the peritoneal reflection. Patients undergoing treatment received the same regimen, except that they received three autologous tumor cell vaccines plus BCG starting approximately 4 to 5 weeks after their operation. Skin testing with standard recall antigens, as well as autologous tumor and mucosa cells, was performed before and after immunotherapy. Patients were followed up frequently for recurrence, and were eligible for surgical resection,