The antitumor action of intravenous endotoxin, intratumor C. parvum, and intravenous cyclophosphamide will be studied in order to illustrate how three different types of immunomodulators can be employed to augment host antitumor defenses sufficiently to cause regression of relatively large established tumors. Experimental design will be based on published evidence showing that progressive growth of immunogenic tumors can evoke the generation of an underlying T cell-mediated concomitant immune response that is down-regulated by suppressor T cells before it develops sufficiently in magnitude to cause tumor regression. 1. The prediction will be tested that successful immunotherapy with intralesional C. parvum is only achievable with very small tumors, because with larger tumors the time required for C. parvum to exert its adjuvant effect overlaps with the time of onset of production of tumor-induced suppressor T cells. It will be determined whether passive transfer of suppressor T cells can inhibit the C. parvum-potentiated production of tumor-sensitixed effector T cells. It also will be determined whether elimination of suppressor T cells by sublethal radiation will allow C. parvum to cause regression of relatively large tumors. 2. Endotoxin will be studied to determine, by passive transfer procedures, whether its ability to cause tumor regression is dependent on the existence in the host of an adequate number of Ly-1+2- T cells that mediate DTH. The possibility also will be investigated as to whether the final effector cell in endotoxin-induced regression is not a lymphocyte but a macrophage that is primed by tumor-sensitized T cells via the secretion of lymphokines to be activated to a tumoricidal state by endotoxin. 3. The immunotherapeutic action of cyclophosphamide will be investigated by employing a cyclophosphamide-resistant tumor to test the prediction that cyclophosphamide-induced regression depends on the ability of the drug to eliminate suppressor T cells and to thereby enable an underlying population of cyclophosphamide-resistant memory T cells to generate a secondary immune response. This will involve showing that the drug cannot cause tumor regression until the host has generated cyclophosphamide sensitive supressor T cells, and cyclophosphamide-resistant menory T cells that are capable of passively transferring immunity to suitable recipients.
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