Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers.

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy Oncolytics Pub Date : 2023-09-16 eCollection Date: 2023-12-19 DOI:10.1016/j.omto.2023.100728
Thanyavi Chinsuwan, Koichi Hirabayashi, Shuji Mishima, Aiko Hasegawa, Miyuki Tanaka, Hidemi Mochizuki, Akihito Shimoi, Takashi Murakami, Shigeki Yagyu, Kimihiro Shimizu, Yozo Nakazawa
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Abstract

Epidermal growth factor receptor (EGFR) is overexpressed in various cancers, including non-small cell lung cancer (NSCLC), and in some somatic cells at a limited level, rendering it an attractive antitumor target. In this study, we engineered chimeric antigen receptor (CAR)-T cells using the piggyBac transposon system, autologous artificial antigen-presenting cells, and natural ligands of EGFR. We showed that this approach yielded CAR-T cells with favorable phenotypes and CAR positivity. They exhibited potent antitumor activity against NSCLC both in vitro and in vivo. When administered to tumor-bearing mice and non-tumor-bearing cynomolgus macaques, they did not elicit toxicity despite their cross-reactivity to both murine and simian EGFRs. In total we tested three ligands and found that the CAR candidate with the highest affinity consistently displayed greater potency without adverse events. Taken together, our results demonstrate the feasibility and safety of targeting EGFR-expressing NSCLCs using ligand-based, piggyBac-engineered CAR-T cells. Our data also show that lowering the affinity of CAR molecules is not always beneficial.

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靶向EGFR的基于配体的piggyBac工程CAR-T细胞对非小细胞肺癌是安全有效的。
表皮生长因子受体(EGFR)在各种癌症中过表达,包括癌症(NSCLC),以及在一些体细胞中以有限的水平过表达,使其成为一种有吸引力的抗肿瘤靶点。在本研究中,我们使用piggyBac转座子系统、自体人工抗原呈递细胞和EGFR的天然配体改造了嵌合抗原受体(CAR)-T细胞。我们发现这种方法产生了具有良好表型和CAR阳性的CAR-T细胞。它们在体外和体内均对NSCLC表现出强大的抗肿瘤活性。当给予荷瘤小鼠和非荷瘤食蟹猴时,尽管它们对小鼠和猴EGFR具有交叉反应性,但它们没有引起毒性。我们总共测试了三个配体,发现具有最高亲和力的CAR候选物始终显示出更大的效力,而没有不良事件。总之,我们的结果证明了使用基于配体的piggyBac工程CAR-T细胞靶向表达EGFR的NSCLC的可行性和安全性。我们的数据还表明,降低CAR分子的亲和力并不总是有益的。
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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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