Beam Therapeutics, Cambridge, MA 02142, USA.
Beam Therapeutics, Cambridge, MA 02142, USA.
Mol Ther. 2024 Oct 2;32(10):3485-3503. doi: 10.1016/j.ymthe.2024.06.022. Epub 2024 Sep 1.
Chimeric antigen receptor (CAR) T cells from allogeneic donors promise "off-the-shelf" availability by overcoming challenges associated with autologous cell manufacturing. However, recipient immunologic rejection of allogeneic CAR-T cells may decrease their in vivo lifespan and limit treatment efficacy. Here, we demonstrate that the immunosuppressants rapamycin and tacrolimus effectively mitigate allorejection of HLA-mismatched CAR-T cells in immunocompetent humanized mice, extending their in vivo persistence to that of syngeneic humanized mouse-derived CAR-T cells. In turn, genetic knockout (KO) of FKBP prolyl isomerase 1A (FKBP1A), which encodes a protein targeted by both drugs, was necessary to confer CD19-specific CAR-T cells (19CAR) robust functional resistance to these immunosuppressants. FKBP1A 19CAR-T cells maintained potent in vitro functional profiles and controlled in vivo tumor progression similarly to untreated 19CAR-T cells. Moreover, immunosuppressant treatment averted in vivo allorejection permitting FKBP1A 19CAR-T cell-driven B cell aplasia. Thus, we demonstrate that genome engineering enables immunosuppressant treatment to improve the therapeutic potential of universal donor-derived CAR-T cells.
嵌合抗原受体 (CAR) T 细胞来自异体供体，通过克服与自体细胞制造相关的挑战，有望实现“现货供应”。然而，受体对异体 CAR-T 细胞的免疫排斥可能会降低其体内寿命并限制治疗效果。在这里，我们证明免疫抑制剂雷帕霉素和他克莫司可有效减轻免疫功能正常的人源化小鼠中 HLA 错配 CAR-T 细胞的同种异体排斥反应，从而延长其体内存活时间至与同基因人源化小鼠衍生的 CAR-T 细胞相当。反过来，编码药物作用靶点 FKBP 脯氨酰异构酶 1A (FKBP1A) 的基因敲除 (KO) 对于赋予 CD19 特异性 CAR-T 细胞（19CAR）对这些免疫抑制剂的强大功能抗性是必要的。FKBP1A 19CAR-T 细胞在体外保持强大的功能特征，并以与未经处理的 19CAR-T 细胞相似的方式控制体内肿瘤进展。此外，免疫抑制治疗避免了体内同种异体排斥反应，从而允许 FKBP1A 19CAR-T 细胞驱动的 B 细胞发育不良。因此，我们证明基因组工程使免疫抑制治疗能够提高通用供体来源的 CAR-T 细胞的治疗潜力。
