TheraVision: Engineering platform technology for the development of oncolytic viruses based on herpes simplex virus type 1

Christina Funk; Nadja Uhlig; Zsolt Ruzsics; Florentin Baur; Matthias Peindl; Sarah Nietzer; Karina Epting; Gabriele Vacun; Gudrun Dandekar; Catherine Botteron; Christian Werno; Thomas Grunwald; Susanne M Bailer

doi:10.1016/j.omton.2024.200784

TheraVision: Engineering platform technology for the development of oncolytic viruses based on herpes simplex virus type 1

Mol Ther Oncol. 2024 Feb 28;32(1):200784. doi: 10.1016/j.omton.2024.200784. eCollection 2024 Mar 21.

Authors

Affiliations

¹ Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Stuttgart, Germany.
² Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.
³ Department for Medical Microbiology and Hygiene, Institute of Virology, University Medical Center Freiburg, Freiburg, Germany.
⁴ Chair of Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Röntgenring, Würzburg, Germany.
⁵ Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies, Würzburg, Germany.
⁶ Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany.

Abstract

Viruses are able to efficiently penetrate cells, multiply, and eventually kill infected cells, release tumor antigens, and activate the immune system. Therefore, viruses are highly attractive novel agents for cancer therapy. Clinical trials with first generations of oncolytic viruses (OVs) are very promising but show significant need for optimization. The aim of TheraVision was to establish a broadly applicable engineering platform technology for combinatorial oncolytic virus and immunotherapy. Through genetic engineering, an attenuated herpes simplex virus type 1 (HSV1) was generated that showed increased safety compared to the wild-type strain. To demonstrate the modularity and the facilitated generation of new OVs, two transgenes encoding retargeting as well as immunomodulating single-chain variable fragments (scFvs) were integrated into the platform vector. The resulting virus selectively infected epidermal growth factor receptor (EGFR)-expressing cells and produced a functional immune checkpoint inhibitor against programmed cell death protein 1 (PD-1). Thus, both viral-mediated oncolysis and immune-cell-mediated therapy were combined into a single viral vector. Safety and functionality of the armed OVs have been shown in novel preclinical models ranging from patient-derived organoids and tissue-engineered human in vitro 3D tumor models to complex humanized mouse models. Consequently, a novel and proprietary engineering platform vector based on HSV1 is available for the facilitated preclinical development of oncolytic virotherapy.

Keywords: BAC; HSV1; MT: Regular Issue; NSCLC; bacterial artificial chromosome technology; combined virus immunotherapy; functionalized virus; mouse models; oncolytic virotherapy; organoids; preclinical models; tissue-engineered tumor models; tumor therapy; virus engineering; virus platform technology.