Protective antitumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumor cell vaccination is mediated by increased Th1-type immunity.
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.
Dredge
Keith
K
Division of Oncology, Department of Oncology, Gastroenterology, Endocrinology, and Metabolism, St. George's Hospital Medical School, Cranmer Terrace, Tooting, London, United Kingdom SW17 0RE. k.dredge@sghms.ac.uk
Marriott
J Blake
JB
Todryk
Stephen M
SM
Muller
George W
GW
Chen
Roger
R
Stirling
David I
DI
Dalgleish
Angus G
AG
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology / Q000627:therapeutic use*; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D008546:Melanoma, Experimental; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D013792:Thalidomide / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019496:Cancer Vaccines; C497965:Cd86 protein, mouse; D016207:Cytokines; D006131:Growth Inhibitors; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D013792:Thalidomide; D007371:Interferon-gamma