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e-Poster Display session

16P - Checkpoint modification of BTLA-HVEM-LIGHT signaling by HSV-1 glycoprotein D (gD) improves vaccine-induced CD8+ T cell responses in pre-clinical cancer models

Date

07 Mar 2022

Session

e-Poster Display session

Presenters

Hildegund Ertl

Citation

Annals of Oncology (2022) 33 (suppl_1): S9-S12. 10.1016/annonc/annonc839

Authors

A. Luber1, X. Zhou2, Z. Xiang2, W. Giles-Davis2, C. Magowan1, H.C. Ertl2

Author affiliations

  • 1 Virion Therapeutics, Newark/US
  • 2 The Wistar Institute, Philadelphia/US
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Abstract 16P

Background

Signaling through the immunoinhibitory B and T lymphocyte attenuator (BTLA), upon binding to the herpes virus entry mediator (HVEM), on dendritic cells, regulates early steps of CD8+ T cell activation. HSV-1 glycoprotein D (gD) attaches to HVEM and blocks BTLA-HVEM inhibitory signaling and allows for co-stimulation through LIGHT, which binds to a different domain on HVEM. Here we present preclinical studies exploring CD8+ T cell responses induced by chimpanzee adenovirus (AdC) vector-based vaccines expressing tumor antigens genetically fused into gD.

Methods

Mice received one or two immunizations with AdC vectors expressing antigens of HPV16 or melanoma, with or without gD. Vaccine-induced CD8+ T cell responses, including their magnitude, functions, duration, specificity profile, and differentiation status were characterized by antibody stains and multicolor flow cytometry in naïve and tumor-bearing mice. Vaccine efficacy was determined in different challenge models, including in combination with anti-PD-1 therapy.

Results

Vaccination with gD-antigen fusion proteins consistently enhanced CD8+ T cell frequencies to the disease-specific antigen, delayed or prevented tumor growth, and improved survival. Addition of gD increased stimulation of CD8+ T cells to subdominant epitopes and thereby enhanced breadth of response. In tumor bearing mice CD8+ T cells induced in presence of gD shows delayed differentiation towards exhaustion. Addition of anti-PD-1 treatment further improved the efficacy of gD-containing tumor vaccines.

Conclusions

Checkpoint modification targeting the HVEM pathway using a genetically encoded gD, fused to a disease-specific antigen, produced potent, prolonged, and broad CD8+ T cell responses across different preclinical studies. Clinical studies to evaluate therapeutic vaccination with gD are planned.

Legal entity responsible for the study

The Wistar Institute and Virion Therapeutics, LLC.

Funding

Virion Therapeutics, LLC.

Disclosure

A. Luber: Financial Interests, Institutional, Ownership Interest, Member BoD: Virion Therapeutics. C. Magowan: Financial Interests, Personal and Institutional, Stocks/Shares, Proprietary Information: Virion Therapeutics. H.C. Ertl: Financial Interests, Personal and Institutional, Leadership Role, Co-founder: Virion Therapeutics; Financial Interests, Institutional, Advisory Role: Freelance, Inc.; Financial Interests, Institutional, Advisory Role: Takeda; Financial Interests, Institutional, Advisory Board: Biogen; Financial Interests, Institutional, Advisory Role: Regenxbio; Non-Financial Interests, Institutional, Advisory Role: Gamaleya Institute; Financial Interests, Institutional, Advisory Board: Ring Therapeutics; Non-Financial Interests, Personal and Institutional, Advisory Board: Canine Rabies Treatment Initiative. All other authors have declared no conflicts of interest.

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