Efficacy of cancer-specific anti-podoplanin CAR-T cells and oncolytic herpes virus G47Δ combination therapy against glioblastoma

Lushun Chalise; Akira Kato; Masasuke Ohno; Sachi Maeda; Akane Yamamichi; Shunichiro Kuramitsu; Satoshi Shiina; Hiromi Takahashi; Sachiko Ozone; Junya Yamaguchi; Yukinari Kato; Yumi Rockenbach; Atsushi Natsume; Tomoki Todo

doi:10.1016/j.omto.2022.07.006

Efficacy of cancer-specific anti-podoplanin CAR-T cells and oncolytic herpes virus G47Δ combination therapy against glioblastoma

Mol Ther Oncolytics. 2022 Jul 20:26:265-274. doi: 10.1016/j.omto.2022.07.006. eCollection 2022 Sep 15.

Authors

Lushun Chalise^{1

2

3}, Akira Kato⁴, Masasuke Ohno⁵, Sachi Maeda¹, Akane Yamamichi⁶, Shunichiro Kuramitsu⁷, Satoshi Shiina⁸, Hiromi Takahashi⁹, Sachiko Ozone⁴, Junya Yamaguchi¹, Yukinari Kato^{10

11}, Yumi Rockenbach⁴, Atsushi Natsume^{4

12}, Tomoki Todo³

Affiliations

¹ Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
² Department of Neurosurgery, Nagoya Central Hospital, Nagoya, Japan.
³ Division of Innovative Cancer Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴ The Institute of Innovation for Future Society, Nagoya University, Nagoya, Japan.
⁵ Department of Neurosurgery, Aichi Cancer Centre Hospital, Nagoya, Japan.
⁶ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Neurosurgery, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
⁸ East Nagoya Imaging Diagnosis Center, Nagoya, Japan.
⁹ Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Nagoya, Japan.
¹⁰ Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.
¹¹ Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.
¹² Department of Neurosugery, Kawamura Medical Society Hospital, Gifu, Japan.

Abstract

Glioblastoma is a devastating malignant brain tumor with a poor prognosis despite standard therapy. Podoplanin (PDPN), a type I transmembrane mucin-like glycoprotein that is overexpressed in various cancers, is a potential therapeutic target for the treatment of glioblastoma. We previously reported the efficacy of chimeric antigen receptor (CAR)-T cells using an anti-pan-PDPN monoclonal antibody (mAb; NZ-1)-based third-generation CAR in a xenograft mouse model. However, NZ-1 also reacted with PDPN-expressing normal cells, such as lymphatic endothelial cells, pulmonary alveolar type I cells, and podocytes. To overcome possible on-target-off-tumor effects, we produced a cancer-specific mAb (CasMab, LpMab-2)-based CAR. LpMab-2 (Lp2) reacted with PDPN-expressing cancer cells but not with normal cells. In this study, Lp2-CAR-transduced T cells (Lp2-CAR-T) specifically targeted PDPN-expressing glioma cells while sparing the PDPN-expressing normal cells. Lp2-CAR-T also killed patient-derived glioma stem cells, demonstrating its clinical potential against glioblastoma. Systemic injection of Lp2-CAR-T cells inhibited the growth of a subcutaneous glioma xenograft model in immunodeficient mice. Combination therapy with Lp2-CAR-T and oncolytic virus G47Δ, a third-generation recombinant herpes simplex virus (HSV)-1, further inhibited the tumor growth and improved survival. These findings indicate that the combination therapy of Lp2-CAR-T cells and G47Δ may be a promising approach to treat glioblastoma.

Keywords: cancer-specific monoclonal antibody-based chimeric antigen receptor T cells; glioma; oncolytic herpes virus; podoplanin.