CELL INTELLIGENCE · 肿瘤细胞治疗研究

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利用异基因 CAR-NKT 细胞克服卵巢癌对 CAR-T 细胞治疗的耐药与逃逸

英文原题：Overcoming ovarian cancer resistance and evasion to CAR-T cell therapy by harnessing allogeneic CAR-NKT cells.

查看英文原题

Overcoming ovarian cancer resistance and evasion to CAR-T cell therapy by harnessing allogeneic CAR-NKT cells.

PubMed 2025/08/12（内容时间） Med Q1 · IF 13.3（JCR 2025）

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技术：CAR-T卵巢癌地区：美国
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研究概要

这些发现凸显了 Allo CAR-NKT 细胞疗法用于卵巢癌的独特疗效与安全性优势，以及其现货型潜力。

中文摘要

背景

传统嵌合抗原受体工程化 T（CAR-T）细胞疗法治疗卵巢癌（OC）面临显著挑战，原因包括肿瘤异质性、铂类耐药、免疫逃逸和免疫抑制性肿瘤微环境（TME）导致的频繁复发。

方法

研究者分析原发 OC 患者样本，发现异体 CAR-NKT（Allo CAR-NKT）细胞有独特机会同时攻击 OC 肿瘤细胞及其 TME。通过干细胞基因工程和临床导向的培养方法，实现了高产量、高纯度地稳定制备 Allo CAR-NKT 细胞。

研究结果

与传统 CAR-T 细胞相比，Allo CAR-NKT 细胞抗 OC 疗效更优，具有多种靶向 OC 的机制、明确的肿瘤归巢能力和显著的 TME 调节作用。Allo CAR-NKT 细胞安全性也较高，CRS 发生率较低。此外，这些细胞不会诱发移植物抗宿主病，并能抵抗宿主免疫细胞介导的异体排斥。

结论

研究结果凸显 Allo CAR-NKT 细胞疗法在疗效和安全性方面的独特优势，以及其作为现货型疗法的潜力。资助：主要经费由加州再生医学研究所（CIRM）提供。

展开英文摘要原文
BACKGROUND

Ovarian cancer (OC) poses a significant challenge for conventional chimeric antigen receptor-engineered T (CAR-T) cell therapy, due to frequent recurrence linked to tumor heterogeneity, platinum resistance, immune evasion, and an immunosuppressive tumor microenvironment (TME).

METHODS

Here, we analyze primary OC patient samples and identify a unique opportunity for allogeneic CAR-NKT ( Allo CAR-NKT) cells to concurrently attack OC tumor cells and their TME. Leveraging stem cell gene engineering and a clinically guided culture method, we achieve robust generation of Allo CAR-NKT cells at high yield and purity.

FINDINGS

Compared to conventional CAR-T cells, Allo CAR-NKT cells demonstrate superior anti-OC efficacy, showcasing multiple OC-targeting mechanisms, focused tumor homing, and pronounced TME modulation. Allo CAR-NKT cells also exhibit a high safety profile with reduced cytokine release syndrome. Additionally, these cells do not induce graft-versus-host disease and resist host immune-cell-mediated allorejection.

CONCLUSIONS

These findings underscore the unique efficacy and safety advantages, as well as the off-the-shelf potential of Allo CAR-NKT cell therapy for OC. FUNDING: Major funding was provided by the California Institute for Regenerative Medicine (CIRM).

论文信息

作者
Li YR、Li Z、Zhu Y、Li M、Chen Y、Lee D、Ochoa CJ、Singh T
第一作者单位
Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA.United States
通讯作者单位
Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA 90095, USA; Goodman-Luskin Microbiome Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: liliyang@ucla.edu.United States
文献类型
美国政府（非公共卫生署）资助研究 · 非美国政府资助研究
期刊
Med (New York, N.Y.)2025 Oct 10
原文标识
PubMed 40803321　·　DOI 10.1016/j.medj.2025.100804

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