mTOR inhibition improves antitumor effects of vaccination with antigen-encoding RNA.
Vaccination with in vitro transcribed RNA encoding tumor antigens is an emerging approach in cancer immunotherapy. Attempting to further improve RNA vaccine efficacy, we have explored combining RNA with immunomodulators such as rapamycin. Rapamycin, the inhibitor of mTOR, was used originally for immunosuppression. Recent reports in mouse systems, however, suggest that mTOR inhibition may enhance the formation and differentiation of the memory CD8(+) T-cell pool. Because memory T-cell formation is critical to the outcome of vaccination approaches, we studied the impact of rapamycin on the in vivo primed RNA vaccine-induced immune response using the chicken ovalbumin-expressing B16 melanoma model in C57BL/6 mice. Our data show that treatment with rapamycin at the effector-to-memory transition phase skews the vaccine-induced immune response toward the formation of a quantitatively and qualitatively superior memory pool and results in a better recall response. Tumor-infiltrating immune cells from these mice display a favorable ratio of effector versus suppressor cell populations. Survival of mice treated with the combined regimen of RNA vaccination with rapamycin is significantly longer (91.5 days) than that in the control groups receiving only one of these compounds (32 and 46 days, respectively). Our findings indicate that rapamycin enhances therapeutic efficacy of antigen-specific CD8(+) T cells induced by RNA vaccination, and we propose further clinical exploration of rapamycin as a component of immunotherapeutic regimens.
Authors' Affiliations: Ganymed Pharmaceuticals, Mainz, Germany.
Mustafa
M
Diken
Sebastian
S
Kreiter
Fulvia
F
Vascotto
Abderraouf
A
Selmi
Sebastian
S
Attig
Jan
J
Diekmann
Christoph
C
Huber
Özlem
Ö
Türeci
Ugur
U
Sahin
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003131:Combined Modality Therapy; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D007156:Immunologic Memory; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D008810:Mice, Inbred C57BL; D012334:RNA, Neoplasm / Q000276:immunology; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014611:Vaccination / Q000379:methods; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D012334:RNA, Neoplasm; D014614:Vaccines, Synthetic; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus