B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells
B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells
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DOI：
10.1182/blood-2011-10-384388
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发表时间：
2012-03-22
期刊：
影响因子：
20.3
通讯作者：
Rosenberg, Steven A.
中科院分区：
文献类型：
--
作者：
Kochenderfer, James N.;Dudley, Mark E.;Rosenberg, Steven A.
我们进行了一项临床试验，以评估过继转移基因修饰的表达抗CD19嵌合抗原受体(CAR)的T细胞。我们的临床方案包括化疗后输注抗CD19转导的T细胞和一个疗程的IL-2。按照我们的方案治疗的8名患者中，有6名患者的晚期进展性B细胞恶性肿瘤得到缓解。在接受该方案治疗的8名患者中，有4名患者长期缺乏正常的多克隆CD19(+)B细胞。所有患者的血液中均检测到含有抗CD19 CAR基因的细胞。在接受治疗的8名患者中，有4名患者的血清炎症细胞因子干扰素-γ和肿瘤坏死因子水平显著升高。急性毒性反应的严重程度与血清干扰素、γ-干扰素和肿瘤坏死因子水平相关。输注的抗CD19-CAR转导的T细胞可能是这些炎性细胞因子的来源，因为我们发现，在体外，在输注抗CD19-CAR转导的T细胞后，外周血T细胞能够以CD19特异性的方式产生肿瘤坏死因子和干扰素-γ。抗CD19-CAR转导的T细胞具有很强的体内清除CD19(+)细胞的能力，有望改善B细胞恶性肿瘤的治疗；然而，CAR转导的T细胞输注后会发生可逆的细胞因子相关的毒性反应。这项试验在ClinicalTrials.gov注册为NCT00924326。(血。2012年；119(12)：2709-2720)
We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor (CAR). Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2. Six of the 8 patients treated on our protocol obtained remissions of their advanced, progressive B-cell malignancies. Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+) B-lineage cells. Cells containing the anti-CD19 CAR gene were detected in the blood of all patients. Four of the 8 treated patients had prominent elevations in serum levels of the inflammatory cytokines IFN gamma and TNF. The severity of acute toxicities experienced by the patients correlated with serum IFN gamma and TNF levels. The infused anti-CD19-CAR-transduced T cells were a possible source of these inflammatory cytokines because we demonstrated peripheral blood T cells that produced TNF and IFN gamma ex vivo in a CD19-specific manner after anti-CD19-CAR-transduced T-cell infusions. Anti-CD19-CAR-transduced T cells have great promise to improve the treatment of B-cell malignancies because of a potent ability to eradicate CD19(+) cells in vivo; however, reversible cytokine-associated toxicities occurred after CAR-transduced T-cell infusions. This trial was registered with ClinicalTrials.gov as NCT00924326. (Blood. 2012; 119(12): 2709-2720)