Akt inhibition at the initial stage of CAR-T preparation enhances the CAR-positive expression rate, memory phenotype and in vivo efficacy.
Akt inhibition at the initial stage of CAR-T preparation enhances the CAR-positive expression rate, memory phenotype and in vivo efficacy.
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CAR-T制备初期抑制Akt可增强CAR阳性表达率、记忆表型和体内功效。
DOI：
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发表时间：
2019-11
影响因子：
5.3
通讯作者：
Junnian Zheng
中科院分区：
文献类型：
--
作者：
Qing Zhang;Jiage Ding;Shishuo Sun;Hongyan Liu;Mengmeng Lu;Xiaohuan Wei;Xiaoge Gao;Xiaokang Zhang;Qiang Fu;Junnian Zheng
嵌合抗原受体修饰 T (CAR-T) 细胞的过继转移是一种新型癌症治疗方法，在血液恶性肿瘤的治疗方面取得了令人鼓舞的突破。输注 CAR-T 细胞的功效与高 CAR 阳性表达率、强烈的增殖反应以及 CAR-T 细胞在体内的持久性有关。制造 CAR-T 细胞的过程通常与输注的 CAR-T 细胞的 CAR 阳性表达率降低和终末分化相关，这会导致 CAR-T 细胞在体内的增殖和持久性降低。因此，制备高CAR阳性表达率、少分化的CAR-T细胞对于临床癌症治疗尤为重要。在这项研究中，我们在 CAR-T 细胞制备的初始阶段，在 Akt 抑制剂 (MK2206) 存在的情况下，转导并扩增了靶向上皮细胞粘附分子 (EpCAM) 的 CAR-T 细胞。我们发现 Akt 抑制剂不会抑制 EpCAM-CAR-T 细胞的增殖或效应功能，但会增加 CAR 阳性表达率并减少终末分化 EpCAM-CAR-T 细胞的数量。此外，使用该方案制备的 EpCAM-CAR-T 细胞似乎具有增强的体内抗肿瘤活性。综上所述，这些研究结果表明，在 CAR-T 细胞制备的初始阶段抑制 Akt 可以提高 CAR-T 细胞的性能。
The adoptive transfer of chimeric antigen receptor-modified T (CAR-T) cells is a novel cancer treatment that has led to encouraging breakthroughs in the treatment of haematological malignancies. The efficacy of infused CAR-T cells is associated with a high CAR-positive expression rate, a strong proliferative response and the persistence of CAR-T cells in vivo. Manufacturing CAR-T cells is a process usually associated with the decreased CAR-positive expression rate and terminal differentiation of the infused CAR-T cells, which causes decreased proliferation and persistence of CAR-T cells in vivo. Therefore, the preparation of a high CAR-positive expression rate and few differentiated CAR-T cells is particularly important for clinical cancer treatment. In this study, we transduced and expanded CAR-T cells targeting the epithelial cell adhesion molecule (EpCAM) in the presence of an Akt inhibitor (MK2206) during the initial stage of CAR-T cell preparation. We show that the Akt inhibitor did not suppress the proliferation or effector function of the EpCAM-CAR-T cells but increased the CAR-positive expression rate and decreased the number of terminally differentiated EpCAM-CAR-T cells. Furthermore, EpCAM-CAR-T cells prepared using this protocol appeared to have enhanced antitumor activity in vivo. Taken together, these findings suggest that Akt inhibition during the initial stage of CAR-T cell preparation could improve the performance of CAR-T cells.
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影响因子：
32.4
作者：
Macintyre AN;Finlay D;Preston G;Sinclair LV;Waugh CM;Tamas P;Feijoo C;Okkenhaug K;Cantrell DA
通讯作者：
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作者：
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影响因子：
45.3
作者：
Kochenderfer, James N.;Somerville, Robert P. T.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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