TY - JOUR
T1 - Demarcated thresholds of tumor-specific CD8 T cells elicited by MCMV-based vaccine vectors provide robust correlates of protection
AU - Beyranvand Nejad, Elham
AU - Ratts, Robert B.
AU - Panagioti, Eleni
AU - Meyer, Christine
AU - Oduro, Jennifer D.
AU - Cicin-Sain, Luka
AU - Früh, Klaus
AU - Van Der Burg, Sjoerd H.
AU - Arens, Ramon
N1 - Publisher Copyright:
© 2019 The Author(s).
PY - 2019/1/31
Y1 - 2019/1/31
N2 - Background: The capacity of cytomegalovirus (CMV) to elicit long-lasting strong T cell responses, and the ability to engineer the genome of this DNA virus positions CMV-based vaccine vectors highly suitable as a cancer vaccine platform. Defined immune thresholds for tumor protection and the factors affecting such thresholds have not well been investigated in cancer immunotherapy. We here determined using CMV as a vaccine platform whether critical thresholds of vaccine-specific T cell responses can be established that relate to tumor protection, and which factors control such thresholds. Methods: We generated CMV-based vaccine vectors expressing the E7 epitope and tested these in preclinical models of HPV16-induced cancer. Vaccination was applied via different doses and routes (intraperitoneal (IP), subcutaneous (SC) and intranasal (IN)). The magnitude, kinetics and phenotype of the circulating tumor-specific CD8 + T cell response were determined. Mice were subsequently challenged with tumor cells, and the tumor protection was monitored. Results: Immunization with CMV-based vaccines via the IP or SC route eliciting vaccine-induced CD8 + T cell responses of > 0.3% of the total circulating CD8 T cell population fully protects mice against lethal tumor challenge. However, low dose inoculations via the IP or SC route or IN vaccination elicited vaccine-induced CD8 + T cell responses that did not reach protective thresholds for tumor protection. In addition, whereas weak pre-existing immunity did not alter the protective thresholds of the vaccine-specific T cell response following subsequent immunization with CMV-based vaccine vectors, strong pre-existing immunity inhibited the development of vaccine-induced T cells and their control on tumor progression. Conclusions: This study highlight the effectiveness of CMV-based vaccine vectors, and shows that demarcated thresholds of vaccine-specific T cells could be defined that correlate to tumor protection. Together, these results may hold importance for cancer vaccine development to achieve high efficacy in vaccine recipients.
AB - Background: The capacity of cytomegalovirus (CMV) to elicit long-lasting strong T cell responses, and the ability to engineer the genome of this DNA virus positions CMV-based vaccine vectors highly suitable as a cancer vaccine platform. Defined immune thresholds for tumor protection and the factors affecting such thresholds have not well been investigated in cancer immunotherapy. We here determined using CMV as a vaccine platform whether critical thresholds of vaccine-specific T cell responses can be established that relate to tumor protection, and which factors control such thresholds. Methods: We generated CMV-based vaccine vectors expressing the E7 epitope and tested these in preclinical models of HPV16-induced cancer. Vaccination was applied via different doses and routes (intraperitoneal (IP), subcutaneous (SC) and intranasal (IN)). The magnitude, kinetics and phenotype of the circulating tumor-specific CD8 + T cell response were determined. Mice were subsequently challenged with tumor cells, and the tumor protection was monitored. Results: Immunization with CMV-based vaccines via the IP or SC route eliciting vaccine-induced CD8 + T cell responses of > 0.3% of the total circulating CD8 T cell population fully protects mice against lethal tumor challenge. However, low dose inoculations via the IP or SC route or IN vaccination elicited vaccine-induced CD8 + T cell responses that did not reach protective thresholds for tumor protection. In addition, whereas weak pre-existing immunity did not alter the protective thresholds of the vaccine-specific T cell response following subsequent immunization with CMV-based vaccine vectors, strong pre-existing immunity inhibited the development of vaccine-induced T cells and their control on tumor progression. Conclusions: This study highlight the effectiveness of CMV-based vaccine vectors, and shows that demarcated thresholds of vaccine-specific T cells could be defined that correlate to tumor protection. Together, these results may hold importance for cancer vaccine development to achieve high efficacy in vaccine recipients.
KW - CMV-based vaccine vector
KW - Cancer
KW - Pre-existing immunity
KW - T cells
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U2 - 10.1186/s40425-019-0500-9
DO - 10.1186/s40425-019-0500-9
M3 - Article
C2 - 30704520
AN - SCOPUS:85060885451
SN - 2051-1426
VL - 7
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 1
M1 - 25
ER -