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, 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.
Mokyr
M B
MB
Department of Biochemistry and Molecular Biology, University of Illinois at Chicago, 60612, USA. Mokyr@uic.edu
Kalinichenko
T
T
Gorelik
L
L
Bluestone
J A
JA
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000187:drug effects* / Q000502:physiology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D060908:CTLA-4 Antigen; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D005260:Female; D018796:Immunoconjugates; D007167:Immunotherapy; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010954:Plasmacytoma / Q000188:drug therapy / Q000628:therapy*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018906:Antineoplastic Agents, Alkylating; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept; D008558:Melphalan