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Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity¹

Keith Dredge^2,*, J. Blake Marriott^*, Stephen M. Todryk^3,, George W. Muller, Roger Chen, David I. Stirling and Angus G. Dalgleish^*

^* Division of Oncology, Department of Oncology, Gastroenterology, Endocrinology, and Metabolism, St. George’s Hospital Medical School, Tooting, London, United Kingdom; Tumor Immunology Group, Institute for Immunology, National University of Ireland, Maynooth, Ireland; and Celgene Corp., Warren, NJ 07059

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- 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- 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.