Josep Carreras Leukaemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
Red Española de Terapias Avanzadas (TERAV) - Instituto de Salud Carlos III (ISCII) (RICORS, RD21/0017/0029).
J Immunother Cancer. 2022 Sep;10(9). doi: 10.1136/jitc-2022-005400.
Chimeric antigen receptor (CAR)-T cells have emerged as a breakthrough treatment for relapse/refractory hematological tumors, showing impressive complete remission rates. However, around 50% of the patients relapse before 1-year post-treatment. T-cell 'fitness' is critical to prolong CAR-T persistence and activity. Allogeneic T cells from healthy donors are less dysfunctional or exhausted than autologous patient-derived T cells; in this context, Delta One T cells (DOTs), a recently described cellular product based on MHC/HLA-independent Vδ1γδ T cells, represent a promising allogeneic platform.
Here we generated and preclinically validated, for the first time, 4-1BB-based CAR-DOTs directed against the interleukin-3α chain receptor (CD123), a target antigen widely expressed on acute myeloid leukemia (AML) blasts.
CD123CAR-DOTs showed vigorous, superior to control DOTs, cytotoxicity against AML cell lines and primary samples both and , even on tumor rechallenge.
Our results provide the proof-of-concept for a DOT-based next-generation allogeneic CAR-T therapy for AML.
嵌合抗原受体 (CAR)-T 细胞已成为复发/难治性血液系统肿瘤的突破性治疗方法，显示出令人印象深刻的完全缓解率。然而，约 50%的患者在治疗后 1 年内复发。T 细胞“适应性”对于延长 CAR-T 持久性和活性至关重要。与自体患者来源的 T 细胞相比，来自健康供体的同种异体 T 细胞功能障碍或衰竭较少；在这种情况下，Delta One T 细胞 (DOTs) 是一种最近描述的基于 MHC/HLA 非依赖性 Vδ1γδ T 细胞的细胞产品，代表了一种有前途的同种异体平台。
我们首次生成并临床前验证了针对白细胞介素 3α 链受体 (CD123) 的基于 4-1BB 的 CAR-DOTs，CD123 是广泛表达于急性髓系白血病 (AML) blasts 上的靶抗原。
CD123CAR-DOTs 对 AML 细胞系和原发性样本均表现出强烈的、优于对照 DOTs 的细胞毒性，即使在肿瘤再挑战时也是如此。
我们的结果为 AML 的基于 DOT 的下一代同种异体 CAR-T 治疗提供了概念验证。
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