肿瘤细胞治疗研究
英文原题：Preferential tumor targeting of HER2 by iPSC-derived CAR T cells engineered to overcome multiple barriers to solid tumor efficacy.
嵌合抗原受体（CAR）T细胞疗法在实体瘤中的应用受到靶向、脱靶毒性、抗原异质性以及无法同时克服肿瘤微环境中多种削弱抗肿瘤活性的耐药机制的制约。
CAR-T细胞疗法治疗实体瘤受多重因素限制，包括靶向肿瘤同时损伤正常组织的毒性、抗原异质性，以及无法同时克服肿瘤微环境中多种不同耐药机制而导致的抗肿瘤活性减弱。本文介绍一种诱导多能干细胞（iPSC）来源的CAR-T细胞，该细胞整合了可区分肿瘤细胞和正常细胞的HER2靶向CAR（并能识别截短和错误折叠的HER2）及多重基因编辑，旨在克服障碍、最大限度提升实体瘤疗效。iPSC来源的HER2靶向CAR-T细胞在体内外均保持强效HER2特异性抗肿瘤活性，同时对HER2⁺正常靶细胞的细胞溶解性攻击有限。联合治疗性抗体后，可通过CAR及高亲和力、不可剪切的CD16a Fc受体实现全面的多抗原靶向。此外，特异性工程化IL-7R融合受体、TGF-β-IL-18R和CXCR2，可实现持久存续、抵抗TGF-β介导的抑制，并特异性迁移至肿瘤部位。
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 (TGF- )-IL-18R, and CXCR2 enabled sustained persistence, resistance to TGF- -mediated suppression, and specific migration to the tumor.
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