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)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030088-10
Application #
3169028
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1981-04-01
Project End
1992-05-31
Budget Start
1990-06-01
Budget End
1991-05-31
Support Year
10
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Ben-Efraim, S (2001) Immunomodulating anticancer alkylating drugs: targets and mechanisms of activity. Curr Drug Targets 2:197-212
Ben-Efraim, S (1999) One hundred years of cancer immunotherapy: a critical appraisal. Tumour Biol 20:1-24
Ben-Efraim, S (1996) Cancer immunotherapy: hopes and pitfalls: a review. Anticancer Res 16:3235-40
Laude, M; Russo, K L; Mokyr, M B et al. (1993) Cure of mice bearing a late-stage, highly metastatic, drug-resistant tumor by adoptive chemoimmunotherapy. Cancer Immunol Immunother 36:229-36
Laude, M; Russo, K L; Mokyr, M B et al. (1993) Two tumor models of curative adoptive chemoimmunotherapy using tumor-infiltrated spleen cells with potent antitumor cytotoxicity stimulated by antigen-sharing tumors. Cancer Immunol Immunother 37:89-96
Laude, M; Siessmann, K L; Mokyr, M B et al. (1991) Advantages of adoptive chemoimmunotherapy with polyethylene glycol-cultured, antigen-activated, tumor-infiltrated spleen cells for the complete eradication of lethal MOPC-315 plasmacytomas. Cancer Res 51:4516-22
Barker, E; Wise, J A; Dray, S et al. (1989) Lysis of antigenically unrelated tumor cells mediated by Lyt 2+ splenic T-cells from melphalan-cured MOPC-315 tumor bearers. Cancer Res 49:5007-15
Wise, J A; Mokyr, M B; Dray, S (1989) Enhancement of the effectiveness of Lyt-2+ T-cells for adoptive chemoimmunotherapy by short-term exposure of tumor-bearer spleen cells to polyethylene glycol and/or melphalan. Cancer Res 49:3613-9
Dray, S; Mokyr, M B (1989) Cyclophosphamide and melphalan as immunopotentiating agents in cancer therapy. Med Oncol Tumor Pharmacother 6:77-85
Wise, J A; Mokyr, M B; Dray, S (1988) Effect of low-dose cyclophosphamide therapy on specific and nonspecific T cell-dependent immune responses of spleen cells from mice bearing large MOPC-315 plasmacytomas. Cancer Immunol Immunother 27:191-7

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