Sonal Dharani, Hana Cho, Jorge Postigo Fernandez, Alexandre Juillerat, Julien Valton, Philippe Duchateau, Laurent Poirot, Shipra Das
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引用次数: 0
摘要
事实证明,使用嵌合抗原受体(CAR)T 细胞的适应性细胞疗法可以挽救许多癌症患者的生命。然而,它对实体瘤的疗效有限。其中一个关键因素是癌症相关成纤维细胞(CAFs),它们会调节肿瘤微环境(TME),抑制 T 细胞浸润并诱发 "T 细胞功能障碍"。此外,肿瘤特异性抗原(TSA)的稀缺性和CAR定向肿瘤相关抗原(TAA)在正常组织上的表达往往会导致 "靶外 "细胞毒性,从而引发安全性问题。利用 TALEN 介导的基因编辑,我们在此介绍一种创新的 CAR-T 细胞工程策略,以克服这些挑战。我们的异体 "智能 CAR T 细胞 "被设计为表达组成型 CAR,靶向实体瘤中的 FAP+ CAFs。此外,第二种靶向肿瘤相关抗原(TAA)(如间皮素)的CAR特异性地整合在TCR信号诱导位点(如PDCD1)上。FAPCAR 介导的 CAF 靶向会诱导间皮素 CAR 的表达,从而建立一个对双重抗原感应敏感的 IF/THEN 门控回路。利用这种方法,我们观察到了增强的抗肿瘤细胞毒性,同时限制了 "靶标外 "毒性。因此,我们的研究展示了 TALEN 介导的基因编辑能力,可用于设计异体 IF/THEN 门控双 CAR T 细胞,有效靶向免疫疗法再现性实体瘤,同时降低潜在的安全风险,从而鼓励这一策略的临床开发。
TALEN-edited allogeneic inducible dual CAR T cells enable effective targeting of solid tumors while mitigating off-tumor toxicity.
Adoptive cell therapy using chimeric antigen receptor (CAR) T cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has been limited in solid tumors. One key factor for this is cancer-associated fibroblasts (CAFs) that modulate the tumor microenvironment (TME) to inhibit T cell infiltration and induce "T cell dysfunction." Additionally, the sparsity of tumor-specific antigens (TSA) and expression of CAR-directed tumor-associated antigens (TAA) on normal tissues often results in "on-target off-tumor" cytotoxicity, raising safety concerns. Using TALEN-mediated gene editing, we present here an innovative CAR T cell engineering strategy to overcome these challenges. Our allogeneic "Smart CAR T cells" are designed to express a constitutive CAR, targeting FAP+ CAFs in solid tumors. Additionally, a second CAR targeting a TAA such as mesothelin is specifically integrated at a TCR signaling-inducible locus like PDCD1. FAPCAR-mediated CAF targeting induces expression of the mesothelin CAR, establishing an IF/THEN-gated circuit sensitive to dual antigen sensing. Using this approach, we observe enhanced anti-tumor cytotoxicity, while limiting "on-target off-tumor" toxicity. Our study thus demonstrates TALEN-mediated gene editing capabilities for design of allogeneic IF/THEN-gated dual CAR T cells that efficiently target immunotherapy-recalcitrant solid tumors while mitigating potential safety risks, encouraging clinical development of this strategy.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.