Although surgery, radiotherapy, and chemotherapy remain the standard weapon in the cancer therapist's arsenal, a number of common human cancers cannot be successfully treated by these methods. With the enormous advances in our understanding of the immune system that have taken place over the past two decades, there has been a growing expectation that immunological approaches to the treatment of cancer will provide new and effective ways to control the disease. Of the several forms of immunotherapy that are being pursued, monoclonal antibodies, cancer vaccines and lymphokines/monokines offer exciting opportunities to harness the extraordinary specificity and efficacy of the immune system in the development of effective cancer therapies. The approach we are taking has been greatly influenced by our laboratory and clinical studies with two IgG3 monoclonal antibodies detecting the gangliosides GD2 and GD3. These antibodies have been shown a) to mediate human complement cytotoxicity and ADCC, b) to induce inflamma- tory reactions in tumor sites, and c) to cause tumor regression in a proportion of patients. In the present proposal, we will extend these findings in melanoma and neuroblastoma, and explore the therapeutic value of inflammatogenic antibodies (IgG2a, IgG3, IgM and IgE) in colon and renal cancer. We will also investigate the ability of cytokines such as TNF, IFN-Y, IL-2 and G-CSF to amplify the selective inflammation induced by monoclonal antibodies at the tumor site, with consequent vascular injury and tumor cell damage. A complementary approach to the use of exogenous cytotoxic antibodies is to induce endogenous antibody production by active immunization with immunogenic cancer antigens. Our past studies have shown that vaccination of melanoma patients with purified GM2 elicits production of IgM antibodies that mediate human complement cytotoxicity for human tumor cells expressing GM2. We plan to continue this approach to active immunization, based on our ongoing search for new immunogenic targets, with the aim of constructing maximally immunogenic vaccines containing glycolipid and glycoprotein antigens that elicit high and sustained levels of circulating cytotoxic antibody. Once this has been achieved, we will test whether antibody induction is associated with delayed tumor recurrence. The unifying theme of this program project is to exploit the biological effector functions of mouse and human antibodies and to augment antibody induced tumor cell injury with lymphokines and monokines.
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