CD19 CAR T cell product and disease attributes predict leukemia remission durability
CD19 CAR T cell product and disease attributes predict leukemia remission durability
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DOI：
10.1172/jci125423
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发表时间：
2019-05-01
影响因子：
15.9
通讯作者：
Jensen, Michael C.
中科院分区：
文献类型：
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作者：
Finney, Olivia C.;Brakke, Hannah;Jensen, Michael C.
背景嵌合抗原受体（CAR）T细胞可以诱导高度难治性白血病和淋巴瘤患者的缓解，但实现持续无复发生存的参数尚未完全确定。我们分析了43名参与确定组成的CD 19 CAR T细胞I期试验的儿童和年轻成人受试者（ClinicalTrials.gov，NCT 02028455）。分析CAR T细胞表型、功能和扩增以及起始材料T细胞库与治疗结果（定义为在63天内实现完全缓解）和无白血病生存期和B细胞再生障碍的持续时间的关系。这些分析揭示，初始治疗失败（n = 5）与过继转移后减弱的CAR T细胞扩增和/或功能性CAR效应细胞的快速消耗相关。与导致持续缓解的产品相比，CAR T产品在表型和功能上相似。然而，最初的单采外周血T细胞可以通过LAG-3（+）/TNF-α（lo）CD 8 T细胞的频率增加以及过继转移后耗竭标志物的快速表达来区分。对于38例达到初始持续微小残留病阴性缓解的受试者，15例仍处于缓解状态，其中10例在CAR T治疗后接受了异基因造血干细胞移植（alloHSCT）。随后的缓解持久性与具有增加的TNF-α分泌CAR CD 8（+）T细胞频率的治疗产品相关，但依赖于输注时足够高的CD 19（+）抗原负荷以触发CAR T细胞增殖。这些参数有可能前瞻性地识别有治疗失败风险的患者，并支持开发在低水平CD 19抗原患者中促进CAR T细胞活化和增殖的方法。
BACKGROUND. Chimeric antigen receptor (CAR) T cells can induce remission in highly refractory leukemia and lymphoma subjects, yet the parameters for achieving sustained relapse-free survival are not fully delineated.METHODS. We analyzed 43 pediatric and young adult subjects participating in a phase I trial of defined composition CD19 CAR T cells (ClinicalTrials.gov,NCT02028455). CAR T cell phenotype, function, and expansion, as well as starting material T cell repertoire, were analyzed in relationship to therapeutic outcome (defined as achieving complete remission within 63 days) and duration of leukemia-free survival and B cell aplasia.RESULTS. These analyses reveal that initial therapeutic failures (n = 5) were associated with attenuated CAR T cell expansion and/or rapid attrition of functional CAR effector cells following adoptive transfer. The CAR T products were similar in phenotype and function when compared with products resulting in sustained remissions. However, the initial apheresed peripheral blood T cells could be distinguished by an increased frequency of LAG-3(+)/TNF-alpha(lo) CD8 T cells and, following adoptive transfer, the rapid expression of exhaustion markers. For the 38 subjects who achieved an initial sustained minimal residual disease-negative remission, 15 are still in remission, 10 of whom underwent allogenic hematopoietic stem cell transplantation (alloHSCT) following CAR T treatment. Subsequent remission durability correlated with therapeutic products having increased frequencies of TNF-alpha-secreting CAR CD8(+) T cells, but was dependent on a sufficiently high CD19(+) antigen load at time of infusion to trigger CAR T cell proliferation.CONCLUSION. These parameters have the potential to prospectively identify patients at risk for therapeutic failure and support the development of approaches to boost CAR T cell activation and proliferation in patients with low levels of CD19 antigen.