Efficacy of cancer-specific anti-podoplanin CAR-T cells and oncolytic herpes virus G47? combination therapy against glioblastoma

被引：36

作者：

Chalise, Lushun ^{[1
,2
,3
]}

Kato, Akira

Ohno, Masasuke ^{[4
]}

Maeda, Sachi ^{[1
]}

Yamamichi, Akane ^{[5
]}

Kuramitsu, Shunichiro ^{[6
]}

Shiina, Satoshi ^{[7
]}

Takahashi, Hiromi ^{[8
]}

Ozone, Sachiko

Yamaguchi, Junya ^{[1
]}

Kato, Yukinari ^{[9
,10
]}

Rockenbach, Yumi ^{[11
]}

Natsume, Atsushi ^{[11
,12
,14
]}

Todo, Tomoki ^{[3
,13
]}

机构：

[1] Nagoya Univ, Dept Neurosurg, Sch Med, Nagoya, Japan

[2] Nagoya Cent Hosp, Dept Neurosurg, Nagoya, Japan

[3] Univ Tokyo, Inst Med Sci, Adv Clin Res Ctr, Div Innovat Canc Therapy, Tokyo, Japan

[4] Aichi Canc Ctr Hosp, Dept Neurosurg, Nagoya, Japan

[5] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA

[6] Nagoya Med Ctr, Dept Neurosurg, Natl Hosp Org, Nagoya, Japan

[7] East Nagoya Imaging Diag Ctr, Nagoya, Japan

[8] Nagoya Univ, Grad Sch Engn, Dept Biomol Engn, Nagoya, Japan

[9] Tohoku Univ, Dept Mol Pharmacol, Grad Sch Med, Sendai, Japan

[10] Tohoku Univ, Dept Antibody Drug Dev, Grad Sch Med, Sendai, Japan

[11] Nagoya Univ, Inst Innovat Future Soc, Nagoya, Japan

[12] Kawamura Med Soc Hosp, Dept Neurosug, Gifu, Japan

[13] Univ Tokyo, Inst Med Sci, Adv Clin Res Ctr, Div Innovat Canc Ther apy, 4 6 1 Shirokanedai,Minato ku, Tokyo 1088639, Japan

[14] Nagoya Univ, Inst Innovat Future Soc, N Room 803, Furo Cho, Chikusa Ku, Nagoya 4648601, Japan

来源：

MOLECULAR THERAPY ONCOLYTICS | 2022年 / 26卷

关键词：

MONOCLONAL-ANTIBODY; ADJUVANT TEMOZOLOMIDE; MARKER; IMMUNOTHERAPY; RADIOTHERAPY; CONCOMITANT; ADENOVIRUS; TUMORS; D2-40;

D O I：

10.1016/j.omto.2022.07.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 therapeu-tic target for the treatment of glioblastoma. We previously re-ported 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. How-ever, 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-ex-pressing 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-ex-pressing 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 G47D, 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 G47D may be a promising approach to treat glioblastoma.

引用

页码：265 / 274

页数：10

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