We will continue to develop active specific immunotherapy for melanoma, one version of which has caused regression in 30% of patients in a Phase I trial, stimulating both cell-mediated immunity and antibodies. Four complementary approaches will be taken: 1) optimization of the clinical regimen, 2) characterization of the phenotype and targets of the cytolytic lymphocytes elicited, 3) analysis of the targets of the serum antibodies, and 4) characterization and purification of the antigens identified by our series of human monoclonal antibodies. First, Phase II trials will be performed to establish a true response rate at the optimal dose determined in Phase I, and to explore a schedule resembling an optimal immunization schema in mice. The clinical regimen will be improved mainly by the use of enriched, more varied, and more purified sources of immunogens. A Phase I trial with one lysate of particular interest will be performed. A Phase II trial of a """"""""polyvalent"""""""" preparation derived from several melanomas will then be conducted with melanoma cell membranes, if they prove to be an enriched source of immunogens. Finally, a large scale Phase III randomized trial will be conducted to measure survival in patients with microscopical residua, with the preparation found to be optimal by then. We will monitor all trails by immunological assays. The frequency of cytolytic lymphocytes will be measured biweekly by limiting dilution assays. Antibodies will also be measured serially by enzyme immunoassay and Western immunoblotting. Skin tests with melanoma lysates and HLA- matched controls will be done before and after treatment. We will characterize the cytolytic lymphocytes, which appear to be nonclassical T cells, by cold target competition assays with various tumors and normal cells. Clones will be established to best determine their identity and targets. The role of HLA determinants as targets or co-determinants in cytolysis will also be explored. Absorption analysis with enzyme immunoassay and Western immunoblotting will be used to see which melanoma antigens elicit serum antibodies, and to localize the antigens in the melanoma cell. Biochemical characterization of the antigens in the interior of the melanoma cell that recognized by our human monoclonal antibodies will be continued. Recombinant DNA technology will be used to clone the antigens, to study their nature and to provide purified materials for future vaccines.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036233-07
Application #
3173747
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1988-03-01
Project End
1990-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Mitchell, M S; Liggett, P E; Green, R L et al. (1994) Sustained regression of a primary choroidal melanoma under the influence of a therapeutic melanoma vaccine. J Clin Oncol 12:396-401
Mitchell, M S; Jakowatz, J; Harel, W et al. (1994) Increased effectiveness of interferon alfa-2b following active specific immunotherapy for melanoma. J Clin Oncol 12:402-11
Quan Jr, W D; Mitchell, M S (1993) Immunology and immunotherapy of melanoma. Cancer Treat Res 65:257-77
Kan-Mitchell, J; Huang, X Q; Steinman, L et al. (1993) Clonal analysis of in vivo activated CD8+ cytotoxic T lymphocytes from a melanoma patient responsive to active specific immunotherapy. Cancer Immunol Immunother 37:15-25
Mitchell, M S; Harel, W; Kan-Mitchell, J et al. (1993) Active specific immunotherapy of melanoma with allogeneic cell lysates. Rationale, results, and possible mechanisms of action. Ann N Y Acad Sci 690:153-66
LeMay, L G; Kan-Mitchell, J; Goedegebuure, P et al. (1993) Detection of melanoma-reactive CD4+ HLA-class I-restricted cytotoxic T cell clones with long-term assay and pretreatment of targets with interferon-gamma. Cancer Immunol Immunother 37:187-94
Mitchell, M S (1992) Chemotherapy in combination with biomodulation: a 5-year experience with cyclophosphamide and interleukin-2. Semin Oncol 19:80-7
Mitchell, M S (1992) Biomodulators in cancer treatment. J Clin Pharmacol 32:2-9
Mitchell, M S (1992) Principles of combining biomodulators with cytotoxic agents in vivo. Semin Oncol 19:51-6
Mitchell, M S; Harel, W; Groshen, S (1992) Association of HLA phenotype with response to active specific immunotherapy of melanoma. J Clin Oncol 10:1158-64

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