Abstract 1854: Cancer treatment utilizing virus-inspired particles for the redirection of immune memory

Abstract

Abstract Cancer resistance is a common clinical outcome following immunotherapy, resulting in a significant unmet need for therapies with alternative and highly differentiated mechanisms of action (MOA). VerImmune has pioneered “Anti-tumor Immune Redirection” (AIR), an approach that repurposes a patient’s pre-existing anti-viral or childhood vaccine immunity towards tumor cells for targeted destruction. Mechanistically, this involves VerImmune’s proprietary platform technology known as AIR-ViPs (Anti-tumor Immune Redirection Virus-inspired Particles). ViPs are based on a modified mouse papillomavirus capsid protein of which 60 copies self-assemble into a 20-30nm T=1 icosahedral structure that are then conjugated on their surface with a CD8+ T cell viral peptide antigen. This peptide conjugated platform specifically targets solid tumors and delivers viral peptide antigens to class I major histocompatibility complex (MHC-1) on the tumor cell surface. This leads to the recognition of the tumor by existing memory viral-specific CD8+ T cells. We show here the three-step MOA of AIR-ViPs. The first step is the specific binding of AIR-ViPs to tumor cells by targeting HSPGs on the tumor cell surface. The binding of ViPs is HSPG-dependent as they do not bind to a HSPG-knockout cell line (PGSA-745). To further assess specificity, we pre-incubated ViPs with varying amounts (100ng/mL-1mg/mL) of heparin which resulted in a dose-dependent decrease in binding where the highest dose of heparin was able to completely block ViP binding to tumor cells. The second step of the MOA is the exogenous loading of the CD8+ T cell-specific peptides onto tumor cell surface MHC class I molecules. To prove this, we demonstrated loading of the SIINFEKL OVA peptide on tumor cells incubated with a SIINFEKL-conjugated AIR-ViP using an antibody that specifically recognizes the SIINFEKL/Kb (MHC-I) complex. We further demonstrate exogenous loading utilizing RMA-S cells that are deficient for MHC-I intracellular processing. The third and final step of the MOA is the redirection of antigen-specific CD8+ T cells to kill tumors following peptide loading. Utilizing an in vitro cytotoxicity assay, which involves co-culturing tumor cells and antigen-specific CD8+ T cells in the presence or absence of AIR-ViPs, specific tumor cell killing was observed and quantified using luciferase which acts as a surrogate for cell viability. Using this assay system and HCMV AIR-VIPs, we showed specific immune redirection of human donor CMV CD8+ T-cell cytotoxicity against several human tumor cell lines incubated with HCMV AIR-VIPs but not with the control unconjugated ViPs. Our results demonstrate the potential of AIR as a tumor antigen-agnostic immunotherapeutic. Additionally, the specificity of ViPs to tumor HSPGs makes AIR potentially applicable across many solid tumors regardless of their origin. Citation Format: Cayce Dorrier, Felagot Abebe, John Troyer, Joshua Wang. Cancer treatment utilizing virus-inspired particles for the redirection of immune memory [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1854.