Article Text

Download PDFPDF

454 Checkpoint modification of early T cell activation provides enhanced anti-tumor activity and survival benefits in a fast-growing preclinical tumor challenge model
  1. Mohsen Mohammadi1,
  2. Xiang Y Zhou1,
  3. Zhi Xiang1,
  4. Wynetta Giles-Davis1,
  5. Andrew Luber2,
  6. Sue L Currie3 and
  7. Hildegund CJ Ertl1
  1. 1The Wistar Institute, Philadelphia, PA, USA
  2. 2Virion Therapeutics, Newark, DE, USA
  3. 3Virion Therapeutics, North Las Vegas, NV, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Checkpoint inhibitors (CPI) that target activated, impaired T cells, have revolutionized cancer treatments. However, there are limited data on CPIs that affect T cell activation. HSV-1 glycoprotein D (gD) binds to the herpes virus entry mediator (HVEM) on dendritic cells and blocks BTLA-HVEM inhibitory signaling during early CD8+ T cell activation. Inhibition of BTLA signaling allows for co-stimulation through LIGHT, which binds to a different domain on HVEM, and enhances and broadens CD8+ T cell responses to the target antigen(s). Here, we report the immunogenicity and efficacy of a chimpanzee adenoviral (AdC) vector expressing sequences of early (E) antigens 2, 5, 6, and 7 of HPV-16, fused into gD (AdC-gDE7652).

Methods Studies were performed in C57/Bl6 mice (n=5–10/group). Frequencies of HPV-16 specific CD8+ T-cells was assessed by intracellular cytokine staining 14 days after a single intramuscular (i.m.) vaccination with AdC vectors encoding HPV-16 E7652 oncoproteins expressed with or without gD. Efficacy was tested in TC-1 challenge studies (5x10^4 to 1x10^6 cells) in mice injected with a single i.m. dose of 1x10^10 vp of AdC-gDE7652, AdC-E7652, or control antigens fused with gD 3 or 9 days after tumor cell transplantation. In some studies, mice were followed for up to 176 days. In mice with growing tumors, T cell functions (granzyme B, perforin, IFN-gamma) and exhaustion markers (PD1, TIM3, LAG3, CTLA4), in spleens and tumors were assessed.

Results The addition of gD increased HPV-16-specific CD8+ T-cell frequencies approximately 10- to 15-fold. In mice vaccinated with AdC-gDE7652, 3 days post TC-1 transplantation, 25/25 (100%) cleared their tumors and remained tumor free, while all (20/20; 100%) of the control-vaccinated mice showed rapid tumor progression. When mice were vaccinated 9 days after TC-1 challenge, the addition of gD doubled the survival time over controls or AdC-E7652-vaccinated animals (60 vs 30 days); T cells within spleens and tumors of AdC-gDE7652 vaccinated animals were polyfunctional and expressed lower levels of exhaustion markers than those of AdC-E7652 or control-vaccinated mice. In 8 mice that previously cleared their tumors, all remained tumor free, upon rechallenge.

Conclusions The addition of gD, an early checkpoint modifier, that provides both checkpoint inhibition and co-stimulation of T cell activation, to an oncogenic target within a vaccine, markedly improves immunogenicity, promotes activation of polyfunctional T cells and enhances tumor clearance and survival with continued protection against rechallenge. A clinical trial evaluating a gD-based vaccine for advanced solid tumors is in development.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.