肿瘤细胞治疗研究
英文原题：The peptide-based bispecific CAR T cells target EGFR and tumor stroma for effective cancer therapy.
The peptide-based bispecific CAR T cells target EGFR and tumor stroma for effective cancer therapy.
我们的研究结果表明，基于肽的双特异性CAR T细胞因其对肿瘤及肿瘤微环境的出色靶向能力，在实体瘤治疗中展现出巨大潜力。
嵌合抗原受体（CAR）-T 细胞对实体瘤的疗效有限，部分原因是缺乏肿瘤特异性抗原和脱靶效应。低分子量肽使 CAR T 细胞能够展示多种抗原受体，以减少脱靶效应。在此，我们开发了一种针对 EGFR 和肿瘤基质的肽基双特异性 CAR，二者在多种肿瘤类型中表达。实验方法与关键结果：肽基 CAR T 细胞表现出优异的增殖、细胞毒活性，并且仅被过表达 EGFR 的肿瘤细胞激活，而不被低表达 EGFR 的正常细胞激活。在小鼠异种移植模型中，肽双特异性 CAR T 细胞能够被递送至肿瘤肿块内部，因此可有效抑制肿瘤生长。同时，它们表现出强大的扩增能力以及在体内维持长期功能的特性。在治疗期间，未在表达较低水平 EGFR 的健康器官上观察到脱肿瘤毒性。结论与
BACKGROUND AND PURPOSE: The efficacy of chimeric antigen receptor (CAR)-T cell for solid tumors is limited partially because of the lack of tumor-specific antigens and off-target effects. Low molecular weight peptides allowed CAR T cell to display several antigen receptors to reduce off-target effects. Here, we develop a peptide-based bispecific CAR for EGFR and tumor stroma, which are expressed in a variety of tumor types. EXPERIMENTAL APPROACH AND KEY RESULTS: The peptide-based CAR T cells show excellent proliferation, cytotoxicity activity and are only activated by tumor cells overexpressing EGFR instead of normal cells with low EGFR expressing. In mouse xenograft models, the peptide bispecific CAR T cells can be delivered into the inner of tumor masses and thus are effective in inhibiting tumor growth. Meanwhile, they show strong expansion capacity and the property of maintaining long-term function in vivo. During treatment, no off-tumor toxicity is observed on healthy organs expressing lower levels of EGFR. CONCLUSIONS & IMPLICATIONS: Our findings demonstrate that peptide-based bispecific CAR T holds great potential in solid tumor therapy due to an excellent targeting ability towards tumors and tumor microenvironment.
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