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Realization of the Therapeutic Potential of CTLA-4 Blockade in Low-Dose Chemotherapy-treated Tumor-bearing Mice¹

Department of Biochemistry and Molecular Biology, University of Illinois at Chicago, Chicago Illinois 60612 [M. B. M., T. K., L. G.], and The Ben May Institute for Cancer Research, The Committee on Immunology, and the Department of Pathology, University of Chicago, Chicago, Illinois 60637 [J. A. B.]

CTLA-4 blockade has been shown by other investigators [D. R. Leach, et al., Science (Washington DC), 271: 1734–1736, 1996; and Y-F. Yang, et al., Cancer Res., 57: 4036–4041, 1997] to retard tumor growth in selected tumor systems. Here, we show that CTLA-4 blockade alone was ineffective in retarding tumor growth in the murine MOPC-315 tumor system. Yet, CTLA-4 blockade offered significant therapeutic benefits to MOPC-315 tumor bearers when combined with a subtherapeutic dose of the chemotherapeutic agent melphalan, which was previously shown (L. Gorelik, et al., Cancer Immunol. Immunother., 39: 117–126, 1994) to shift the cytokine profile in the tumor bearers toward type-1 cytokines. In addition, we show here that anti-CTLA-4 monoclonal antibody enhanced antitumor cytotoxicity when the anti-CTLA-4 monoclonal antibody was added to stimulation cultures of spleen cells from low-dose melphalan-treated MOPC-315 tumor-bearing mice but not from untreated tumor-bearing mice. These results suggest that the therapeutic benefits of CTLA-4 blockade depend on the ability of drugs such as melphalan to promote an immunogenic environment by altering the cytokine profile of tumor-specific T cells.

¹ Supported by Research Grant CA-76532 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at the Department of Biochemistry and Molecular Biology (M/C 536). The University of Illinois at Chicago, 1819 West Polk Street, Chicago, IL 60612. E-mail: Mokyr@uic.edu.

Received 9/ 2/98. Accepted 10/19/98.

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