Customized Multifunctional Peptide Hydrogel Scaffolds for CAR-T-Cell Rapid Proliferation and Solid Tumor Immunotherapy
Customized Multifunctional Peptide Hydrogel Scaffolds for CAR-T-Cell Rapid Proliferation and Solid Tumor Immunotherapy
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用于CAR-T细胞快速增殖和实体瘤免疫治疗的定制多功能肽水凝胶支架
DOI：
10.1021/acsami.2c10727
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发表时间：
2022-08-24
影响因子：
9.5
通讯作者：
Yang, Pengxiang
中科院分区：
文献类型：
--
作者：
Jie, Jing;Mao, Duo;Yang, Pengxiang
car - t细胞疗法必须扩大以快速获得大量效应细胞，而目前的技术无法解决这一挑战。较长的手术时间会使CAR-T细胞对治疗的反应丧失或改变其功能和表型，也会使患者失去最佳治疗时间。目前，较低的生存时间和归巢效率降低了CAR-T在体内的抗肿瘤作用。但是没有人能在一个系统中解决这两个问题，该系统具有类似的淋巴器官微环境来激活/扩大免疫治疗的细胞递送。在这里，我们基于一种自组装肽生成了人工定制的免疫细胞基质支架，以根据CAR-T的特点保存和增强细胞表型。一体化纳米级基质支架将CAR-T的处理时间缩短至3天，与传统方案相比增加了10倍以上。细胞结合调节机械转导和化学信号，模拟基质支架表现出最佳的刚度和粘附配体密度，从而加速car - t细胞增殖。同时，工程化car - t分泌的内在PD-1阻断单链可变片段（scFv）通过旁分泌和自分泌方式抵抗自身和肿瘤微环境，进一步增强细胞增殖和细胞毒性。与传统的CAR-T治疗相比，从支架中局部递送CAR-T细胞可以显著地实现长期保留，抑制肿瘤生长，并增加效应T细胞的浸润。生物工程和基因工程方法的应用导致了快速培养环境的发展，可以控制car - t细胞和癌症的基质支架特性
CAR-T-cell therapies must be expanded to obtain a large number of effector cells quickly, and the current technology cannot address this challenge. A longer operational time would lose or alter the function and phenotype of CAR-T cells in response to therapy, and it also causes a loss in the optimal treatment time for patients. At present, lower survival time and homing efficiency reduce the antitumor effect of CAR-T in vivo. But nobody has solved these two issues in one system, which has a similar microenvironment of lymphoid organs to activate/expand cell delivery for immunotherapy. Here, we generated artificial, customized immune cell matrix scaffolds based on a self-assembling peptide to preserve and augment the cell phenotype in light of the characteristics of CAR-T. The all-in-one nanoscale matrix scaffolds reduced the processing time of CAR-T to 3 days and resulted in over a 10-fold increase compared with the traditional protocol. The cells were combined to modulate mechanotransduction and chemical signals, and the mimic matrix scaffolds showed optimal stiffness and adhesive ligand density, thereby accelerating CAR-T-cell proliferation. Meanwhile, engineering CAR-T-secreted intrinsic PD-1 blocking single-chain variable fragments (scFv) further increased cell proliferation and cytotoxicity by resisting the self and tumor microenvironment in a paracrine and autocrine manner. Local delivery of CAR-T cells from the scaffolds significantly enabled long-term retention, suppressed tumor growth, and increased infiltration of effector T cells compared with traditional CAR-T treatment. The application of bioengineering and genetic engineering approaches has led to the development of rapid culture environments that can control matrix scaffold properties for CAR-T-cell and cancer