Abstract 268: Engineering a novel epithelial-tropic pseudovirus platform for targeted gene therapy to carcinomas.

Abstract Carcinomas represent over 80% of all cancer diagnoses and remain difficult to treat due to genetic heterogeneity, acquired drug resistance, and limited therapeutic specificity. Oncolytic viral therapies (OVTs) have shown promise for many cancers; however, current platforms such as the modified herpes simplex virus rely on intratumoral delivery and remain highly immunogenic, restricting their use against deep-seated and metastatic epithelial malignancies. To address this, we developed a non-replicative pseudotyped lentiviral platform designed with epithelial tropism and stable genomic integration. Our engineered chimeric envelope surface receptor retains key native receptor interactions of the L1 capsid protein of the human papilloma virus, designed in-silico to exploit functional domains, while preserving vital molecular mechanisms. This glycoprotein, combined with lentiviral backbone elements, yields a morphologically intact virion, confirmed by negative-stain TEM, that avoids virus-like-particle formation prior to plasma membrane trafficking. Transduction assays demonstrated selective infection and sustained transgene expression in epithelial cell lines as opposed to non-epithelial controls. To enhance selectivity, cancer-specific promoters would further confine payload expression to malignant epithelial cells. The pseudovirus can deliver a larger payload (8-10 kb) greater than that of Adeno-Associated Virus (≤ 4.7 kb) supporting complex therapeutic cassettes, including suicide genes and barrier-repair payloads. Our ongoing in-vitro and in-vivo studies are evaluating therapeutic delivery and efficacy in specific carcinoma models. Citation Format: Kendall Wesley Knechtel, Daniel Pelaez. Engineering a novel epithelial-tropic pseudovirus platform for targeted gene therapy to carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 268.