This NATIONAL COOPERATIVE ANTI-CANCER MODEL DEVELOPMENT GROUP (NCAMDG) proposal seeks to develop a new, spontaneous metastasis model of human malignant melanoma to explore strategies for effective cancer treatment that allows an in-depth investigation of the interactions between a growing metastatic tumor and the human immune system. This model will be established in mice with genetically determined immunodeficiency, that are injected with human peripheral leukocytes (SCID-hu). In addition, this proposal seeks to make use of this same metastasis model in athymic (nu//nu) mice, where it is presently operative, and to compare the efficacy, of these two anti-cancer models to develop new cancer treatment modalities. Specifically, the two anti-cancer models will serve to critically evaluate the antiproliferative effects of chimeric mouse-human monoclonal antibodies (chMabs) against receptors for epidermal growth factor (EGF-R) and melanotransferrin (MTr); novel chimeric antibody-interleukin-2 and tumor necrosis factor fusion proteins, bispecific antibodies recognizing EGF-R or MTr and T cell markers such as CD3 and CD2, and recombinant fusion proteins consisting of chimeric Mabs and the cytotoxic domain of Pseudomonas exotoxin. The participants in this cooperative agreement include scientists from the Research Institute of Scripps Clinic, La Jolla, CA and Damon Biotech, Inc., Needham Heights, MA. Close productive collaborations between these scientists in studies with chimeric recombinant Mabs to ganglioside antigens have already led to clinical phase I trials in collaboration with clinical centers selected by the Biological Response Modifier Program, NCI. Project I presents an overview and an administrative budget. Project II deals with the development of chimeric recombinant Mabs and novel fusion proteins, consisting of chimeric Mab and cytokines or growth factors. In Projects III and IV, the spontaneous metastatic tumor model will be developed in SCID-hu mice and compared to the same model already operative in athymic (nu/nu) mice. Both, Projects 3 and 4 also deal with the optimization of these mouse systems as anti-cancer models of metastatic disease and with the evaluation of anti-tumor effects of the various hybrid chimeric antibody-fusion proteins. It is anticipated that the proposed experiments will lead to novel anti-cancer models and to new cancer treatment modalities that can be evaluated in future phase I clinical trials with those chimeric Mabs and their recombinant constructs that show promise of anti-tumor effects in novel animal models of spontaneous metastasis of human malignant melanoma.
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