CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia.
CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia.
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作者：
Kenderian SS;Ruella M;Shestova O;Klichinsky M;Aikawa V;Morrissette JJ;Scholler J;Song D;Porter DL;Carroll M;June CH;Gill S
化疗难治性急性髓性白血病（AML）患者预后不良。嵌合抗原受体T（CART）细胞疗法在CD19+恶性肿瘤中产生了令人兴奋的结果，并可能克服传统白血病疗法的许多局限性。我们使用吉妥珠单抗ozogamicin（克隆My96）中使用的抗CD33单链可变片段开发了靶向CD33（CART 33）的CART细胞，并测试了这些细胞的活性和毒性。CART 33在体外表现出显著的效应子功能，并导致AML异种移植物中白血病的根除和存活期的延长。CART 33还在造血毒性的异种移植模型中导致人谱系血细胞减少和骨髓祖细胞减少，表明永久表达的CD33特异性CART细胞将具有不可接受的毒性。为了增强CART 33作为AML的选择的活力，我们设计了瞬时表达的mRNA抗CD33 CAR。通过电穿孔将基因转移到T细胞中，并导致高水平表达，具有针对AML的有效但自限的活性。因此，我们的临床前研究显示了CART 33的有效活性，并表明通过RNA修饰的抗CD33 CAR的瞬时表达可用于患者以避免长期骨髓抑制。CART 33疗法可以单独使用或作为难治性AML中同种异体移植前的准备方案的一部分。
Patients with chemo-refractory acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T (CART) cell therapy has produced exciting results in CD19+ malignancies and may overcome many of the limitations of conventional leukemia therapies. We developed CART cells to target CD33 (CART33) using the anti-CD33 single chain variable fragment used in gemtuzumab ozogamicin (clone My96) and tested the activity and toxicity of these cells. CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts. CART33 also resulted in human lineage cytopenias and reduction of myeloid progenitors in xenograft models of hematopoietic toxicity, suggesting that permanently expressed CD33-specific CART cells would have unacceptable toxicity. To enhance the viability of CART33 as an option for AML, we designed a transiently expressed mRNA anti-CD33 CAR. Gene transfer was carried out by electroporation into T cells and resulted in high-level expression with potent but self-limited activity against AML. Thus our preclinical studies show potent activity of CART33 and indicate that transient expression of anti-CD33 CAR by RNA modification could be used in patients to avoid long-term myelosuppression. CART33 therapy could be used alone or as part of a preparative regimen prior to allogeneic transplantation in refractory AML.