T Cells Expressing Chimeric Antigen Receptors Can Cause Anaphylaxis in Humans
T Cells Expressing Chimeric Antigen Receptors Can Cause Anaphylaxis in Humans
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DOI：
10.1158/2326-6066.cir-13-0006
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发表时间：
2013-07-01
影响因子：
10.1
通讯作者：
June, Carl H.
中科院分区：
文献类型：
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作者：
Maus, Marcela V.;Haas, Andrew R.;June, Carl H.
通过整合载体表达嵌合抗原受体（CAR）， T细胞可以重新定向以克服对癌症的耐受性。在临床前模型中，我们之前已经表明，转染编码CAR的mRNA的T细胞是一种具有抗肿瘤功效的替代策略，并且由于短暂的mRNA CAR表达，有可能安全地评估新CAR靶点的靶向非肿瘤毒性。在这里，我们报告了在4例患者中观察到的安全性，这些患者接受了自体T细胞治疗，这些T细胞被电穿孔，编码一种来自小鼠人间皮素抗体的CAR。由于CAR在T细胞上表达的短暂性，临床研究中的受试者被反复输注CAR-T细胞以评估其安全性。一名受试者在完成第三次输注后几分钟内出现过敏反应和心脏骤停。虽然已知人类抗小鼠免疫球蛋白（Ig）G抗体会与car转导的T细胞一起产生，但它们一直被认为没有不良的临床后果。这是CAR修饰T细胞引起的临床过敏反应的第一个描述，最有可能是通过CAR特异性的IgE抗体。这些结果表明，来源于小鼠抗体的car的潜在免疫原性可能是mRNA car的安全性问题，特别是当使用间歇给药计划时。AACR (C) 2013人。
T cells can be redirected to overcome tolerance to cancer by engineering with integrating vectors to express a chimeric antigen receptor (CAR). In preclinical models, we have previously shown that transfection of T cells with mRNA coding for a CAR is an alternative strategy that has antitumor efficacy and the potential to evaluate the on-target off-tumor toxicity of new CAR targets safely due to transient mRNA CAR expression. Here, we report the safety observed in four patients treated with autologous T cells that had been electroporated with mRNA coding for a CAR derived from a murine antibody to human mesothelin. Because of the transient nature of CAR expression on the T cells, subjects in the clinical study were given repeated infusions of the CAR-T cells to assess their safety. One subject developed anaphylaxis and cardiac arrest within minutes of completing the third infusion. Although human anti-mouse immunoglobulin (Ig)G antibodies have been known to develop with CAR-transduced T cells, they have been thought to have no adverse clinical consequences. This is the first description of clinical anaphylaxis resulting from CAR-modified T cells, most likely through IgE antibodies specific to the CAR. These results indicate that the potential immunogenicity of CARs derived from murine antibodies may be a safety issue for mRNA CARs, especially when administered using an intermittent dosing schedule. (C)2013 AACR.