State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China .
Hum Gene Ther. 2018 May;29(5):626-639. doi: 10.1089/hum.2017.241. Epub 2018 Mar 19.
Acute myeloid leukemia (AML) is a kind of a malignant hematologic tumor caused by uncontrolled repopulation of myeloid hematopoietic stem cells (HSCs). Current therapeutic effects for AML patients are unsatisfactory. In particular, relapsed and refractory AML still have a poor prognosis. T cells modified by chimeric antigen receptor (CAR) was an immunotherapeutic strategy for malignancies, which has a broad developing prospect. Most AML cells overexpress the myeloid antigen CD33. Therefore, CD33-specific CAR-T cells with different co-stimulators (CD28, 4-1BB, or both, referred to as CD33 28z.CAR-T cells, CD33 BBz.CAR-T cells, or CD33 28BBz.CAR-T cells, respectively) were developed to evaluate their efficacy against AML. The effectiveness of three types of CD33 CAR-T cells against AML was verified by specific killing effect to AML cells and prolonged survival of a xenograft mouse model. In terms of CAR-T cell efficacy, especially when transfused into human bodies, the persistence of T cells is also an important index, as it is closely associated with the long-term effect of CAR-T cells. Therefore, the characteristics of three types of CD33 CAR-T cells related to the persistence of T cells were examined. It was found that during expansion, CD33 BBz.CAR-T cells had an increased central memory compartment, while CD33 28z.CAR-T cells were predominantly effector memory T cells. In addition, CD33 28z.CAR-T cells were more inclined to become exhausted. The study suggests that incorporation of 4-1BB in CARs may endow T cells with long-lasting survival ability, thus improving the long-term anti-leukemia effect of CAR-T cells, especially when transfused to the human body.
急性髓系白血病（AML）是一种由髓系造血干细胞（HSCs）不受控制的再增殖引起的恶性血液肿瘤。目前 AML 患者的治疗效果并不令人满意。特别是复发和难治性 AML 仍然预后不良。嵌合抗原受体（CAR）修饰的 T 细胞是一种针对恶性肿瘤的免疫治疗策略，具有广阔的发展前景。大多数 AML 细胞过度表达髓样抗原 CD33。因此，开发了具有不同共刺激分子（CD28、4-1BB 或两者都有，分别称为 CD33 28z.CAR-T 细胞、CD33 BBz.CAR-T 细胞或 CD33 28BBz.CAR-T 细胞）的 CD33 特异性 CAR-T 细胞来评估它们对 AML 的疗效。三种类型的 CD33 CAR-T 细胞对 AML 的有效性通过对 AML 细胞的特异性杀伤作用和异种移植小鼠模型的生存延长得到了验证。在 CAR-T 细胞疗效方面，特别是在输入人体时，T 细胞的持久性也是一个重要指标，因为它与 CAR-T 细胞的长期效果密切相关。因此，研究了三种类型的 CD33 CAR-T 细胞与 T 细胞持久性相关的特征。研究发现，在扩增过程中，CD33 BBz.CAR-T 细胞中央记忆区增加，而 CD33 28z.CAR-T 细胞主要为效应记忆 T 细胞。此外，CD33 28z.CAR-T 细胞更容易衰竭。研究表明，在 CAR 中加入 4-1BB 可能赋予 T 细胞持久的生存能力，从而提高 CAR-T 细胞的长期抗白血病效果，特别是在输入人体时。
