36P - Therapeutic vaccination with HPV-16 oncoproteins fused into a checkpoint modifier of early T cell activation protects against HPV-associated tumors in a preclinical model

Background

Checkpoint inhibition(CPI) by antibodies against PD-1, CTLA-4 and other immunoinhibitors has revolutionized cancer treatment. However, there are limited data on CPIs that target the activation phase of adaptive immune responses. 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 signaling and allows for co-stimulation through LIGHT, which binds to a different domain on HVEM. BTLA blockade, in turn, enhances and broadens CD8⁺ T cell responses to a target antigen. Here, we report the immunogenicity and efficacy of a chimpanzee adenoviral vector (AdC) vaccine expressing a novel sequence derived from the early proteins 2, 5, 6 and 7 of HPV-16 fused into gD (AdC-gDE7652).

Methods

The frequency of HPV-16-specific CD8⁺ T-cells was assessed with intracellular cytokine staining in C57/Bl6 or HLA-A2 mice after a single IM vaccination with AdC vectors encoding HPV-16 E7652 oncoproteins expressed within gD or without gD. Efficacy was tested in a standard (5x10ˆ4 cells) dose TC-1 tumor cell challenge model with mice receiving a single IM injection of AdC-gDE7652 or AdC expressing HIV gag fused within gD (AdC-gDgag) 3 days after tumor cell transplantation. Mice were followed for 80 days.

Results

The addition of gD increased HPV-16 -specific CD8+ T-cell frequencies approximately 15-fold. In the standard TC-1 challenge experiment, 100% (n = 10) of the AdC-gDE7652 vaccinated animals experienced regression and complete tumor loss by day 25; this was sustained through day 80. In contrast, 100% (n=10) of the AdC-gDgag vaccinated animals experienced rapid tumor growth and death by day 21.

Conclusions

These preclinical data demonstrated that the addition of gD, an early checkpoint modifier, which acts locally at the site of T cell stimulation, to an HPV-16 vaccine markedly improves the vaccine’s immunogenicity and efficacy. A clinical study evaluating this construct, in HPV-16 induced cancers and precancerous lesions, is in development.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Virion Therapeutics Llc.

Disclosure

S.L. Currie: Financial Interests, Personal, Stocks/Shares: Virion Therapeutics. A. Luber: Financial Interests, Personal, Ownership Interest: Virion Therapeutics. H.C. Ertl: Other, Personal and Institutional, Leadership Role, Co-founder: Virion Therapeutics; Other, Personal, Advisory Role: Biogen, Regenxbio; Other, Personal, Advisory Board: Ring Therapeutics, Canine Rabies Treatment Initiative. All other authors have declared no conflicts of interest.