Abstract
The use of immunotherapy as it relates to the treatment of solid tumor malignancies appears to be an effective approach for managing many patients who present with both recurrent and metastatic disease. This holds true, especially in those cases where patients have failed current chemotherapeutic protocols and evidence of tumor progression is noted. In such instances, the delivery of the proper immunotherapeutic agents may be effective either alone or in combination with chemotherapy. The ideal approach would be in the identification of an immunogenic protein that characterized and was specific for the tumor system to be treated. One of the first attempts to utilize specific active immunotherapy for treating cancer patients with advanced disease was by Ariel Hollinshead. She produced several vaccine preparations composed of tumor associated antigen (TAA) derived from pooled allogeneic tumor membrane preparations. These vaccines, obtained from operative specimens were shown to exhibit varying degrees of improvement in the overall survival of such patients. They were employed in treating patients with advanced malignancies including those having lung cancer, colon cancer and malignant melanoma. For most who received the vaccine following resection of an advanced disease process, survival results demonstrating 80-90% freedom of disease at 5 years could be achieved. These results were considered significant when compared to other therapeutic protocols available at the time. Further use in clinical trials were held back at the suggestion of the FDA due to possible viral contamination in the next set of vaccine preparations if any tumor specimen used contained the possible presence virulent strains of virus such as hepatitis, AIDS and HPV. At this point recombinant vaccines were felt to be essential if such vaccines were to be used in future clinical trials. Monoclonal antibodies were therefore developed against each of the pooled vaccine preparations and used for affinity purification and sequencing of the antigens. In reviewing our survival data results it became apparent that those who failed therapy were patients unable to mount an effective IgG1 response and not related to the presence of CD8 T cells. The mAbs were now produced in GMP format and clinical trials as such were initiated for patients with recurrent colon and pancreatic Ca having failed standard chemotherapy.
Highlights
Much of the original work with the newly developed tumor associated antigen (TAA) vaccines of Hollinshead [1], utilized background information derived from Prehn’s experiments with animal tumors [2,3]
To determine which of these antigenic groups contained the proper immunogenic material for use in the vaccine preparation, patients with the disease of concern as well as other cancers were skin tested with material obtained from the Sephadex preparations, for signs of delayed hypersensitivity reactions (DHR)
The early results suggest that the procedure we have developed offers better than 90% sensitivity and specificity. When this enzyme linked immunoabsorbent assay (ELISA) protocol is fully implemented, see below and employed in monitoring patients, it will be the first step in introducing these newer monoclonals as part of an overall approach in cancer management, that is the use of a single immunogenic monoclonal antibody for both diagnose and for treating and monitoring the tumor [16]
Summary
Much of the original work with the newly developed TAA vaccines of Hollinshead [1], utilized background information derived from Prehn’s experiments with animal tumors [2,3]. Regional bands obtained from these gels were skin tested again in order to narrow down the relatively purified preparation that would eventually be employed in the immunization process It was important, that once a relatively purified preparation of antigen was obtained, that the level of TAA necessary to turn on the full immune response in patients be defined. On completion of the colon and lung immunotherapy trials in 1988, FDA was approached with the possibility of employing this form of therapy in more extensive trials with the goal of commercialization, considering the beneficial responses that had been achieved in the clinical studies They suggested that for any further vaccine preparations or for new clinical trials to be initiated, one would have to provide the antigen in the form of recombinant protein. These immunogenic molecules appeared to represent post translational modifications of the original proteins found in the fetal state following demethylation of the gene whose product was essential for fetal development
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