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Vaccines for the 21st Century: A Tool for Decisionmaking
inhibited replication but not immunogenicity, and then vaccinated patients with three monthly injections at two different doses, half the dose intradermal and half subcutaneous. Researchers didn’t expect and didn’t find any toxicity; the important results were immunological.
In order to determine whether paracrine elaboration of GM-CSF generated human immune responses, patients were randomized in a double-blind fashion to receive either irradiated tumor cells or irradiated tumor cells transduced with the GM-CSF gene. DTH was chosen as the simplest and most reproducible assay for in vivo immune response. A total of 30 days after vaccination, 1 million nontransduced cells were injected at a distant site, and the diameter of induration, edema, and erythema was measured to determine DTH response.
When the blind was broken, the results indicated that the lower vaccine dose (4 million cells) did not induce significant immune responses. However, the higher dose (40 million cells) did produce some fairly impressive DTH responses in patients who had received the GM-CSF-transduced vaccine. Even more encouraging were the results of the biopsy analysis of infiltrates at the DTH site. In addition to the quantitative difference, roughly 50 percent of the infiltrating cells in GM-CSF-transduced patients were eosinophils, whereas no eosinophils were found infiltrating the DTH sites of nontransduced patients. This was the same result observed in animal tests.
Anecdotally, one of the three patients that received the higher dose of transduced vaccine showed a fairly significant clinical response. This patient had multiple pulmonary metastases from his renal cancer that had progressed very rapidly over the 2 months between surgery and initial vaccination. After 1 vaccination, there was evidence of regression, and after the third vaccination there was a 95-percent reduction in the volume of metastatic tumor. While anecdotal, this suggests that there may be a therapeutic correlate to the observed immune response.
Allogeneic Vaccines. In these renal cancer patients, as in the melanoma patients discussed above, the vaccine did not induce a response against normal tissue; patients showed no impairment or autoimmunity of their remaining kidney, just as melanoma patients did not develop vitiligo. This suggests that it should be possible to generate responses against them without generating a clinically prohibitive autoimmune disease. At the same time, there is mounting evidence that the immunorelevant antigens in tumors are shared, as was the case in the MAGE proteins (see above).
This may provide a rationale for using a genetically modified allogeneic vaccine. Tumor antigens are presented to T-cells not by the tumor but by APCs derived from host bone marrow. This implies that it may not be necessary to match HLA between the vaccine and the patient. Certainly, generic vaccines would be far less labor-intensive and less expensive than individualized vaccines, and—since quantities would no longer be limited by the growth potential