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
收藏
页码：265 / 274
页数：10
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