Vaccine site inflammation potentiates idiotype DNA vaccine-induced therapeutic T cell-, and not B cell-, dependent antilymphoma immunity.
Lymphoma idiotype protein vaccines have shown therapeutic potential in previous clinical studies, and results from a completed pivotal, phase 3 controlled trial are promising. However, streamlined production of these patient-specific vaccines is required for eventual clinical application. Here, we show that second-generation, chemokine-fused idiotype DNA vaccines, when combined with myotoxins that induced sterile inflammation with recruitment of antigen-presenting cells at vaccination sites, were exceptional in their ability to provoke memory antitumor immunity in mice, compared with several TLR agonists. The combined vaccination strategy elicited both antigen-specific T-cell responses and humoral immunity. Unexpectedly, vaccine-induced tumor protection was intact in B cell-deficient mice but was abrogated completely by T-cell depletion in vivo, suggesting T-cell dependence. Furthermore, the optimal effect of myotoxins was observed with fusion vaccines that specifically targeted antigen delivery to antigen-presenting cells and not with vaccines lacking a targeting moiety, suggesting that the rational vaccine design will require combination strategies with novel, proinflammatory agents and highly optimized molecular vaccine constructs. These studies also challenge the paradigm that antibody responses are the primary of idiotype-specific antitumor effects and support the optimization of idiotype vaccines designed to induce primarily T-cell immunity.
Qin
Hong
H
Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Cha
Soung-chul
SC
Neelapu
Sattva S
SS
Lou
Yanyan
Y
Wei
Jinsong
J
Liu
Yong-Jun
YJ
Kwak
Larry W
LW
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004179:Cobra Cardiotoxin Proteins / Q000008:administration & dosage; D003439:Crotoxin / Q000008:administration & dosage; D004357:Drug Synergism; D007111:Immunity, Cellular; D007130:Immunoglobulin Idiotypes / Q000008:administration & dosage; D007249:Inflammation / Q000276:immunology; D008223:Lymphoma / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage*
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D004179:Cobra Cardiotoxin Proteins; D007130:Immunoglobulin Idiotypes; D019444:Vaccines, DNA; D003439:Crotoxin