Bahram Valamehr团队取得一项新突破。他们的最新研究提出了利用iPSC衍生的CAR-T细胞克服实体瘤疗效的多重障碍，优先靶向HER2肿瘤。相关论文于2025年6月4日发表在《细胞—干细胞》杂志上。

研究团队描述了一种诱导多能干细胞（iPSC）衍生的CAR-T细胞，它结合了人类表皮生长因子受体2 （HER2）靶向CAR-T细胞，与正常细胞区分识别肿瘤，并能够检测截断和错误折叠的HER2，通过多重编辑，旨在解决和克服障碍，最大限度地提高实体肿瘤适应症的疗效。iPSC衍生的HER2定向CAR-T细胞在体外和体内都保持了强大的HER2特异性抗肿瘤活性，对HER2+正常靶标的细胞溶解作用有限。与治疗性抗体的结合，通过CAR和高亲和力、不可切割的CD16a Fc受体，实现了全面的多抗原靶向。此外，白细胞介素(IL)-7R-fusion，转化生长因子β (TGF-β)-IL-18R和CXCR2的特异性工程使其持续存在，抵抗TGF-β介导的抑制，并特异性迁移到肿瘤。

研究人员表示，嵌合抗原受体（CAR） T细胞治疗实体肿瘤受到靶标、非肿瘤毒性、抗原异质性以及无法同时克服肿瘤微环境中多种不同的耐药机制的限制，这些机制会减弱抗肿瘤活性。

附：英文原文

Title: Preferential tumor targeting of HER2 by iPSC-derived CAR T cells engineered to overcome multiple barriers to solid tumor efficacy

Author: Martin P. Hosking, Soheila Shirinbak, Kyla Omilusik, Shilpi Chandra, Mika K. Kaneko, Angela Gentile, Susumu Yamamoto, Bishwas Shrestha, Joy Grant, Megan Boyett, Demetrio Cardenas, Hannah Keegan, Samad Ibitokou, Carolina Pavon, Takahiro Mizoguchi, Tatsuya Ihara, Daisuke Nakayama, Ramzey Abujarour, Tom T. Lee, Raedun Clarke, Jode Goodridge, Eigen Peralta, Tatsuo Maeda, Junichi Takagi, Takao Arimori, Yukinari Kato, Bahram Valamehr

Issue&Volume: 2025-06-04

Abstract: Chimeric antigen receptor (CAR) T cell therapies in solid tumors have been limited by on-target, off-tumor toxicity, antigen heterogeneity, and an inability to simultaneously overcome multiple diverse resistance mechanisms within the tumor microenvironment that attenuate anti-tumor activity. Here, we describe an induced pluripotent stem cell (iPSC)-derived CAR T cell that combines a human epidermal growth factor receptor 2 (HER2)-targeting CAR—differentially recognizing tumor from normal cells and enabling detection of both truncated and misfolded HER2—with multiplex editing designed to address and overcome obstacles to maximize efficacy in solid tumor indications. The iPSC-derived, HER2-directed CAR T cells maintained potent HER2-specific anti-tumor activity in both in vitro and in vivo settings, with limited cytolytic targeting of HER2+ normal targets. Combination with therapeutic antibodies enabled comprehensive multi-antigen targeting through both the CAR and a high-affinity, non-cleavable CD16a Fc receptor. Additionally, specific engineering of interleukin (IL)-7R-fusion, transforming growth factor β (TGF-β)-IL-18R, and CXCR2 enabled sustained persistence, resistance to TGF-β-mediated suppression, and specific migration to the tumor.

DOI: 10.1016/j.stem.2025.05.007

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00187-0