靶向CD19 CAR-T缓解异基因造血干细胞移植后的 B 细胞恶性肿... - 中国病毒学论坛|我们一直在坚持！

AllogeneicT Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissionsof B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-CellTransplantation Without Causing Graft-Versus-Host Disease.

Progressive malignancy is the leading cause of deathafter allogeneic hematopoietic stem-cell transplantation (alloHSCT). AfteralloHSCT, B-cell malignancies often are treated with unmanipulated donorlymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are noteffective at eradicating malignancy and often cause graft-versus-host disease,a potentially lethal immune response against normal recipient tissues.

We conducted a clinical trial of allogeneic T cellsgenetically engineered to express a chimeric antigen receptor (CAR) targetingthe B-cell antigen CD19. Patients with B-cell malignancies that had progressedafter alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies wereadministered. The T cells were obtained from each recipient's alloHSCT donor.

Eight of 20 treated patients obtained remission, whichincluded six complete remissions (CRs) and two partial remissions. The responserate was highest for acute lymphoblastic leukemia, with four of five patients obtainingminimal residual disease-negative CR. Responses also occurred in chroniclymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30months in a patient with chronic lymphocytic leukemia. New-onset acutegraft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities includedfever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtainedremissions than in those who did not. Programmed cell death protein-1 expressionwas significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusionCAR T-cell levels.

Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies thatprogress after alloHSCT. The findings point toward a future whenantigen-specific T-cell therapies will play a central role in alloHSCT.

逐步的恶性肿瘤进展是导致异基因造血干细胞移植之后导致死亡的主要原因。异基因造血干细胞移植之后，B细胞恶性肿瘤患者进常会注入供者没有加工过的淋巴细胞(DLIs)。DLIs通常不能有效的消除恶性肿瘤，并且常常会引起移植物抗宿主病，一个潜在的攻击正常组织的致死性免疫反应。

我们进行了同种异体的转基因表达靶向B 细胞抗原CD19 的嵌合抗原受体(CAR)T 细胞的临床试验。B细胞恶性淋巴患者在异基因移植之后注射CAR-T细胞。不使用化疗和其他治疗方式。T细胞是从每个受试者的异基因供者体内提取。

20位患者中有8位获得了缓解，6个完全缓解一节2个部分缓解。对于急性淋巴细胞瘤的有效率最好，5个中有4个获得了完全的缓解。有效率也出现在慢性淋巴细胞白血病和淋巴细胞瘤中。最长的持续性的完全缓解是慢性淋巴细胞性白血病患者，缓解时间超过 30 个月。这些病人中没有出现一个急性移植物抗宿主病，毒副反应包括了发热、心动过速、低血压。完全缓解的患者血液中CAR-T的浓度比没有缓解的患者高。

同种异体靶向CD19 CAR- T 细胞能有效地治疗 B 细胞恶性肿瘤的进展后。调查结果说明将来，CAR-T细胞疗法将在异基因造血干细胞移植中发挥关键作用。