Live-attenuated lymphocytic choriomeningitis virus-based vaccines for active immunotherapy of HPV16-positive cancer

Infection with human papillomavirus (HPV) is associated with a variety of cancer types and limited therapy options. Therapeutic cancer vaccines targeting the HPV16 oncoproteins E6 and E7 have recently been extensively explored as a promising immunotherapy approach to drive durable antitumor T cell i...

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Bibliographic Details
Published in:Oncoimmunology 2020-01, Vol.9 (1), p.1809960-1809960
Main Authors: Schmidt, Sarah, Bonilla, Weldy V., Reiter, Andrea, Stemeseder, Felix, Kleissner, Theresa, Oeler, Daniel, Berka, Ursula, El-Gazzar, Ahmed, Kiefmann, Bettina, Schulha, Sophie C., Raguz, Josipa, Habbeddine, Mohamed, Scheinost, Marilies, Qing, Xiaoping, Lauterbach, Henning, Matushansky, Igor, Pinschewer, Daniel D., Orlinger, Klaus K.
Format: Article
Language:English
Subjects:
Cancer vaccine
HPV16 E6 E7
HPV16-positive cancer
LCMV
mouse tumor model
Original Research
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Summary:Infection with human papillomavirus (HPV) is associated with a variety of cancer types and limited therapy options. Therapeutic cancer vaccines targeting the HPV16 oncoproteins E6 and E7 have recently been extensively explored as a promising immunotherapy approach to drive durable antitumor T cell immunity and induce effective tumor control. With the goal to achieve potent and lasting antitumor T cell responses, we generated a novel lymphocytic choriomeningitis virus (LCMV)-based vaccine, TT1-E7E6, targeting HPV16 E6 and E7. This replication-competent vector was stably attenuated using a three-segmented viral genome packaging strategy. Compared to wild-type LCMV, TT1-E7E6 demonstrated significantly reduced viremia and CNS immunopathology. Intravenous vaccination of mice with TT1-E7E6 induced robust expansion of HPV16-specific CD8 + T cells producing IFN-γ, TNF-α and IL-2. In the HPV16 E6 and E7-expressing TC-1 tumor model, mice immunized with TT1-E7E6 showed significantly delayed tumor growth or complete tumor clearance accompanied with prolonged survival. Tumor control by TT1-E7E6 was also achieved in established large-sized tumors in this model. Furthermore, a combination of TT1-E7E6 with anti-PD-1 therapy led to enhanced antitumor efficacy with complete tumor regression in the majority of tumor-bearing mice that were resistant to anti-PD-1 treatment alone. TT1-E7E6 vector itself did not exhibit oncolytic properties in TC-1 cells, while the antitumor effect was associated with the accumulation of HPV16-specific CD8 + T cells with reduced PD-1 expression in the tumor tissues. Together, our results suggest that TT1-E7E6 is a promising therapeutic vaccine for HPV-positive cancers.
ISSN:2162-402X
2162-4011
2162-402X
DOI:10.1080/2162402X.2020.1809960