A single injection of less than one-tenth of the maximal tolerable dose of cyclophosphamide or melphalan cures a BALB/c mouse bearing a large subcutaneous MOPC-315 plasmacytoma and extensive metastases at a late stage of tumor growth, yet the same dose of drug has little or no curative effect for a small nonpalpable tumor at an early stage of tumor growth. The cure of the mouse is due primarily to potent T-cell-dependent antitumor immunity that emerges shortly after drug administration, partially as a result of drug-mediated elimination of the immunosuppressive activity of macrophages and tumor cells, and brings about the eradication of a large tumorigenic load that remains after the drug has been cleared from the circulation. The immunosuppressed spleens exposed to active forms of the drugs either in vivo or in vitro developed a greatly enhanced antitumor immune potential as assessed by the ability of the spleen cells to become cytotoxic for the tumor cells upon in vitro immunization with mitomycin C-treated tumor cells. After exposure to nontoxic levels of the drug, the macrophages and tumor cells lost their suppressive activity. Moreover, the tumor cells developed strong immunostimulatory activity and a subpopulation of T cells appeared with enhanced immunopotentiating activity. Thus, the low dose of drug acts as an immunomodulator to shift the balance from immunosuppression to potent antitumor immunity in blocking the immunosuppressive effects of macrophages and tumor cells, by enhancing the immunogenicity of the tumor cells, and by inducing the appearance of immunopotentiating T cells. The cross-linking ability of the drugs was not essential for the immunomodulatory effects observed, since these effects were also observed with a monofunctional drug. That a low dose of drug may be effective in the eradication of a large late-stage metastatic tumor, primarily due to its immunomodulatory activity, has important implications for the design of cancer therapy. As a direct result of this research project, a pilot study for therapy of untreated myeloma patients with Stage I disease has been initiated in collaboration with William H. Knospe, M.D. as part of the program of the Eastern Cooperative Oncology Group. (IT)