A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy

多重耐药性重组的CAR-T细胞与异基因相免疫疗法的

结合

The adoptive transfer of chimeric antigen receptor (CAR) T cell represents a highly promising strategy to fight against multiple cancers. The clinical outcome of such therapies is intimately linked to the ability of effector cells to engraft, proliferate, and specifically kill tumor cells within patients. When allogeneic CAR T-cell infusion is considered, host versus graft and graft versus host reactions must be avoided to prevent rejection of adoptively transferred cells, host tissue damages and to elicit significant antitumoral outcome. This work proposes to address these three requirements through the development of multidrug-resistant T cell receptor αβ-deficient CAR T cells. We demonstrate that these engineered   T cells displayed efficient antitumor activity and proliferated in the presence of purine and pyrimidine nucleoside analogues, currently used in clinic as preconditioning lymphodepleting regimens. The absence of TCRαβ at their cell surface along with their purine nucleotide analogues-resistance properties could prevent their alloreactivity and enable them to resist to lymphodepleting regimens that may be required to avoid their ablation via HvG reaction. By providing a basic framework to develop a universal T cell compatible with allogeneic adoptive transfer, this work is laying the foundation stone of the large-scale utilization of CAR T-cell immunotherapies.

爱康得生物医学编译：

嵌合抗原受体T细胞的过继免疫治疗在多种肿瘤的治疗中具有广阔的前景。这种疗法的临床结果和效应细胞在患者体内并在体的增殖能力，以及特异性杀死肿瘤细胞的能力密切相关。当同种异体CAR-T细胞输注体内时，必须避免宿主抗移植物和移植物抗宿主反应，以防止机体排斥过继移植的细胞或移植的细胞对宿主组织损害，但同时也要保证对宿主肿瘤的杀伤作用。这项工作中作者提出研发多重耐药T细胞受体αβ缺陷CAR-T细胞的三个要求，证明了这些重组的细胞显示出了有效的抗肿瘤活性以及在嘌呤，嘧啶核苷类似物作用下的增殖能力：这些类似物目前在临床上被广泛用作在预处理淋巴细胞方案中。由于这些新型CAR-T细胞表面没有TCRαβ，因此它们的具备抵抗嘌呤核苷酸类似物抗性性能，可以防止由这些药物引起的淋巴细胞的消融。作者希望通过这一个基本的框架来开发可在同种异体过继免疫治疗中使用的通用T细胞，这项工作是铺设大规模利用CAR-T细胞免疫治疗的基石。

A Multidrug-resistant Engineered CAR T Cell for Allo~.pdf
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