Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice

CTLA-4 blockade has been shown by other investigators [D. R. Leach, at at, Science (Washington DC), 271: 1734-1736, 1996; and Y-F. Yang, et at, Cancer Res., 57: 4036-4041, 1997] to retard tumor growth in selected tumor system s, Here, we show that CTLA-4 blockade alone was ineffective in retarding tu mor growth in the murine MOPC-315 tumor system, Yet, CTLA-4 blockade offere d significant therapeutic benefits to MOPC-315 tumor bearers when combined with a subtherapeutic dose of the chemotherapeutic agent melphalan, which w as previously shown (L. Gorelik, st at, Cancer Immunol, Immunother., 39: 11 7-126, 1994) to shift the cytokine profile in the tumor bearers toward type -1 cytokines, In addition, we show here that anti-CTLA-4 monoclonal antibod y enhanced antitumor cytotoxicity when the anti-CTLA-4 monoclonal antibody was added to stimulation cultures of spleen cells from Low-dose melphalan-t reated MOPC-315 tumor-bearing mice but not from untreated tumor-bearing mic e. These results suggest that the therapeutic benefits of CTLA-4 blockade d epend on the ability of drugs such as melphalan to promote an immunogenic e nvironment by altering the cytokine profile of tumor-specific T cells.