Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Retroviral Replicating Vector Toca 511 (vocimagene amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer

Hiroki Kushiya
,
Kei Hiraoka
,
Tomohiro Suzuki
,
Kazuho Inoko
,
Akihito Inagaki
,
Hiroki Niwa
,
Katsunori Sasaki
,
Toru Nakamura
,
Takahiro Tsuchikawa
,
Toshiaki Shichinohe
,
Douglas J. Jolly
,
Noriyuki Kasahara
* ORCID logo ,
Satoshi Hirano
Version 1 : Received: 30 June 2022 / Approved: 1 July 2022 / Online: 1 July 2022 (15:28:59 CEST)

How to cite: Kushiya, H.; Hiraoka, K.; Suzuki, T.; Inoko, K.; Inagaki, A.; Niwa, H.; Sasaki, K.; Nakamura, T.; Tsuchikawa, T.; Shichinohe, T.; Jolly, D. J.; Kasahara, N.; Hirano, S. Retroviral Replicating Vector Toca 511 (vocimagene amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer. Preprints 2022, 2022070015. https://doi.org/10.20944/preprints202207.0015.v1 Kushiya, H.; Hiraoka, K.; Suzuki, T.; Inoko, K.; Inagaki, A.; Niwa, H.; Sasaki, K.; Nakamura, T.; Tsuchikawa, T.; Shichinohe, T.; Jolly, D. J.; Kasahara, N.; Hirano, S. Retroviral Replicating Vector Toca 511 (vocimagene amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer. Preprints 2022, 2022070015. https://doi.org/10.20944/preprints202207.0015.v1

Abstract

Therapeutic efficacy of retroviral replicating vector (RRV)-mediated prodrug activator gene therapy has been demonstrated in a variety of tumor models, but clinical investigation of this approach has so far been restricted to glioma and gastrointestinal malignancies. In the present study, we evaluated replication kinetics, transduction efficiency, and therapeutic efficacy of RRV in experimental models of lung cancer. RRV delivering GFP as a reporter gene showed rapid viral replication in a panel of lung cancer cells in vitro, as well as robust intratumoral replication and high levels of tumor transduction in subcutaneous and orthotopic pleural dissemination models of lung cancer in vivo. Toca 511 (vocimagene amiretrorepvec), a clinical-stage RRV encoding optimized yeast cytosine deaminase (yCD) which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU), showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies.

Keywords

lung cancer; gene therapy; retrovirus vector

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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