Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies
Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies
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DOI：
10.1073/pnas.1524155113
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发表时间：
2016-01-26
影响因子：
11.1
通讯作者：
Young, Travis S.
中科院分区：
文献类型：
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作者：
Rodgers, David T.;Mazagova, Magdalena;Young, Travis S.
嵌合抗原受体T（CAR-T）细胞疗法在B细胞恶性肿瘤的临床试验中取得了令人印象深刻的结果。然而，一旦输注到患者体内，与无法控制CAR-T细胞相关的安全性问题仍然是一个重大挑战。在这里，我们报告了基于重组抗体的双功能开关的工程化，该双功能开关由移植有肽新表位的肿瘤抗原特异性Fab分子组成，该肽新表位仅与肽特异性可转换CAR-T细胞（sCAR-T）结合。开关通过免疫突触的选择性形成来重定向生物正交sCAR-T细胞的活性，其中sCAR-T细胞、开关和靶细胞以结构上定义和时间上控制的方式相互作用。在B细胞白血病的Nalm-6异种移植啮齿动物模型中，对CD 19具有特异性的优化开关以剂量滴定方式控制sCAR-T细胞的活性、组织归巢、细胞因子释放和表型。可以调整sCAR-T细胞给药方案，以提供与相应的常规CART-19相当的功效，但具有较低的细胞因子水平，从而提供在临床转化中减轻细胞因子释放综合征的方法。此外，我们证明了这种方法很容易适用于使用相同的sCAR-T细胞靶向癌细胞上的CD 20，这表明这种方法可能广泛适用于异质性和耐药肿瘤群体，以及其他液体和实体肿瘤抗原。
Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR-T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens.