Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity

• Published in: The Journal of immunology (1950) 2002-05, Vol.168 (10), p.4914-4919
• Main Authors: Dredge, Keith, Marriott, J. Blake, Todryk, Stephen M, Muller, George W, Chen, Roger, Stirling, David I, Dalgleish, Angus G
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - administration & dosage; Animals; Antigens, CD - biosynthesis; Antineoplastic Combined Chemotherapy Protocols - immunology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B7-1 Antigen - biosynthesis; B7-2 Antigen; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; Cells, Cultured; Coculture Techniques; Cytokines - biosynthesis; Growth Inhibitors - administration & dosage; Growth Inhibitors - immunology; Histocompatibility Antigens Class I - biosynthesis; Injections, Intraperitoneal; Injections, Subcutaneous; Interferon-gamma - biosynthesis; Melanoma, Experimental; Membrane Glycoproteins - biosynthesis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasm Transplantation - immunology; Spleen - cytology; Spleen - immunology; Spleen - metabolism; T-Lymphocyte Subsets - immunology; Th1 Cells - immunology; Thalidomide - administration & dosage; Thalidomide - analogs & derivatives; Tumor Cells, Cultured - immunology; Tumor Cells, Cultured - metabolism; Tumor Cells, Cultured - pathology; Tumor Cells, Cultured - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.10.4914

Thalidomide and its novel T cell costimulatory analogs (immunomodulatory drugs) are currently being assessed in the treatment of patients with advanced cancer. However, neither tumor-specific T cell costimulation nor effective antitumor activity has been demonstrated in vivo. In this study, we assessed the ability of an immunomodulatory drug (CC-4047/ACTIMID) to prime a tumor-specific immune response following tumor cell vaccination. We found that the presence of CC-4047 during the priming phase strongly enhanced antitumor immunity in the vaccinated group, and this correlated with protection from subsequent live tumor challenge. Protection was associated with tumor-specific production of IFN-gamma and was still observed following a second challenge with live tumor cells 60 days later. Furthermore, CD8(+) and CD4(+) splenocyte fractions from treated groups secreted increased IFN-gamma and IL-2 in response to tumor cells in vitro. Coculture of naive splenocytes with anti-CD3 mAb in the presence of CC-4047 directly costimulated T cells and increased Th1-type cytokines. Our results are the first to demonstrate that a costimulatory thalidomide analog can prime protective, long-lasting, tumor-specific, Th1-type responses in vivo and further support their ongoing clinical development as novel anti-cancer agents.