c-JUN 增强 CRISPR 敲入抗 B7-H3 CAR T 细胞在小细胞肺癌及胸部 SMARCA4 缺陷型未分化肿瘤中的功能

英文原题：c-JUN enhances CRISPR knockin anti-B7-H3 CAR T cell function in small cell lung cancer and thoracic SMARCA4-deficient undifferentiated tumors.

PubMed 2026/01/20（内容时间） Cell Rep Med Q1 · IF 14（JCR 2025）

技术：CAR-T 技术：基因编辑小细胞肺癌地区：美国

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研究概要

小细胞肺癌（SCLC）是一种高度致命的疾病，其通过下调主要组织相容性（MHC）I 类分子限制 T 细胞应答。

中文摘要

小细胞肺癌（SCLC）是一种高度致死性疾病，可通过下调主要组织相容性复合体（MHC）I类分子限制T细胞应答。嵌合抗原受体（CAR）T细胞不受MHC限制，因此可能成为治疗SCLC的有效策略。然而，目前已知的SCLC CAR靶点很少。本文显示，B7-H3/CD276在SCLC以及胸部SMARCA4缺陷型未分化肿瘤（UT）中表达，后者在临床病理特征上可模拟SCLC。胸部SMARCA4缺陷型UT可通过分泌转化生长因子β1（TGF-β1）限制B7-H3 CAR-T细胞杀伤。为克服肿瘤驱动的CAR-T细胞抑制，我们利用CRISPR-Cas9将c-JUN与B7-H3 CAR共同敲入原代人T细胞的TRAC位点。非病毒法制备的c-JUN+B7-H3 CAR-T细胞增强了对抗原密度较低的SCLC细胞及胸部SMARCA4缺陷型UT的杀伤能力，为应对这些高度侵袭性肿瘤提供了平台。我们还证明，c-JUN+B7-H3 CAR-T细胞可通过符合GMP规范的临床规模流程制备。

展开英文摘要原文

Small cell lung cancer (SCLC), a highly lethal disease, limits T cell responses by downregulating major histocompatibility (MHC) class I molecules. Because chimeric antigen receptor (CAR) T cells are not MHC restricted, they may provide a powerful strategy against SCLC. However, few CAR targets for SCLC are known. Here, we show that B7-H3/CD276 is expressed in SCLC and thoracic SMARCA4-deficient undifferentiated tumors (UTs) that can clinicopathologically mimic SCLC. Thoracic SMARCA4-deficient UTs limit killing by B7-H3 CAR T cells via secretion of transforming growth factor 1 (TGF- 1). To overcome tumor-driven CAR T cell suppression, we knock in c-JUN alongside a B7-H3 CAR into the TRAC locus of primary human T cells utilizing CRISPR-Cas9. Non-viral c-JUN+B7-H3 CAR T cells show enhanced killing of both SCLC cells with low antigen density and thoracic SMARCA4-deficient UTs, providing a platform to address these highly aggressive entities. We also provide evidence that good manufacturing practice (GMP) clinical-scale manufacturing is feasible for c-JUN+B7-H3 CAR T cells.

论文信息

作者: Balke-Want H、Keerthi V、Del Carmen Arenas M、Chen Y、Malipatlolla M、Klysz DD、Xu P、Ho K
第一作者单位: Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany; Cancer Center Cologne Essen (CCCE), Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.United States
通讯作者单位: Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Weill West Coast Cancer Hub, Stanford, CA, USA; Division of Blood and Marrow Transplantation and Cell Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Laboratory for Cell and Gene Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: feldmans@stanford.edu.United States
期刊: Cell reports. Medicine2026 Jan 20

原文标识: PubMed 41564857　·　DOI 10.1016/j.xcrm.2025.102549

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