Cancer Invest Downloaded from informahealthcare.com by Mcgill University on 01/08/15 For personal use only.
Cancer Investigation, 8(2) 281-282 (1990)
Tumor-Specific BCG Therapy in Colon Cancer Herbert C. Hoover Jr. and Michael G. Hanna Jr.* Division of Surgical (%cology Massachusetts General Hospital Boston, Massachusetts 021 14 'Organon Teknika Rockv~lie,Maryland 20850
Over the past ten years, we have translated this animal model into a prospectively randomized, controlled clinical trial in patients with colorectal cancer. The objectiveshave 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,
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 immunotherapymodel. 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 demonstratedthe 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 intradermalvaccination sites were found to be critical. It was possible in this model to demonstrate that neither allogeneiccells, dead cells, or cell components(antigenic extracts) were effective. It was also demonstrated that BCG components were not effective substitutesfor whole, viable BCG cells. Neither autologoustumor cells or BCG alone were effective in this model. 28 1
Hoover and Hanna
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systemic chemotherapy, or infusional therapy, depending upon the extent and site of recurrence. No serious side effects were demonstratedin any of the immunized patients. The only morbidity was that of the ulcer that formed at the site of the first two vaccines. These healed in all patients. We have previously reported that immunized patients showed a significant increase in the DCH response to autologous tumor cells. With a median postoperative followup of over five years, we are finding a significant improvement in the time to recurrence in colon cancer patients, but not in those with rectal cancer. Survival data await further followup. With such small numbers of patients, we cannot conclude that AS1 is of proven
therapeutic benefit. That will require expansion of this study and completionof a multi-institutionaltrial currently underway through the Eastern Cooperative Oncology Group.
REFERENCES 1. Hoover HC JR,Brandhorst J, Peters L et al: Adjuvant active specific immunotherapy for human colorectal cancer-five year follow up of a prospectively randomized trial. To be submitted.
2. Hoover HC Jr, Surdyke M, Hanna MG et al: Prospectively randomized trial of adjuvant active specific immderapy for human colorectal cancer. Cancer 551236-1234, 1985.
Cancer Investigation, 8(2) 281-282 (1990)
Tumor-Specific BCG Therapy in Colon Cancer Herbert C. Hoover Jr. and Michael G. Hanna Jr.* Division of Surgical (%cology Massachusetts General Hospital Boston, Massachusetts 021 14 'Organon Teknika Rockv~lie,Maryland 20850
Over the past ten years, we have translated this animal model into a prospectively randomized, controlled clinical trial in patients with colorectal cancer. The objectiveshave 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,
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 immunotherapymodel. 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 demonstratedthe 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 intradermalvaccination sites were found to be critical. It was possible in this model to demonstrate that neither allogeneiccells, dead cells, or cell components(antigenic extracts) were effective. It was also demonstrated that BCG components were not effective substitutesfor whole, viable BCG cells. Neither autologoustumor cells or BCG alone were effective in this model. 28 1
Hoover and Hanna
Cancer Invest Downloaded from informahealthcare.com by Mcgill University on 01/08/15 For personal use only.
282
systemic chemotherapy, or infusional therapy, depending upon the extent and site of recurrence. No serious side effects were demonstratedin any of the immunized patients. The only morbidity was that of the ulcer that formed at the site of the first two vaccines. These healed in all patients. We have previously reported that immunized patients showed a significant increase in the DCH response to autologous tumor cells. With a median postoperative followup of over five years, we are finding a significant improvement in the time to recurrence in colon cancer patients, but not in those with rectal cancer. Survival data await further followup. With such small numbers of patients, we cannot conclude that AS1 is of proven
therapeutic benefit. That will require expansion of this study and completionof a multi-institutionaltrial currently underway through the Eastern Cooperative Oncology Group.
REFERENCES 1. Hoover HC JR,Brandhorst J, Peters L et al: Adjuvant active specific immunotherapy for human colorectal cancer-five year follow up of a prospectively randomized trial. To be submitted.
2. Hoover HC Jr, Surdyke M, Hanna MG et al: Prospectively randomized trial of adjuvant active specific immderapy for human colorectal cancer. Cancer 551236-1234, 1985.
