Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma
Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma
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DOI：
10.1182/blood-2013-03-490565
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发表时间：
2013-08-08
期刊：
影响因子：
20.3
通讯作者：
June, Carl H.
中科院分区：
文献类型：
--
作者：
Linette, Gerald P.;Stadtmauer, Edward A.;June, Carl H.
癌症免疫治疗的障碍是T细胞受体（TCR）对肿瘤中表达的抗原的亲和力通常较低。我们启动了表达针对HLA-A*01限制性MAGE-A3的亲和力增强的TCR的工程化T细胞的临床测试。启动了开放标签方案，以测试骨髓瘤和黑色素瘤患者的TCR。前两名接受治疗的患者发生心源性休克，并在T细胞输注后几天内死亡，这是高亲和力TCR临床前研究无法预测的事件。尸检的大体结果显示严重的心肌损伤，组织病理学分析显示T细胞浸润。在心脏尸检组织中未检测到MAGE-A3表达。在两名患者中记录了体内工程化T细胞的稳健增殖。由诱导多能干细胞产生的跳动的心肌细胞培养物触发了T细胞杀伤，这是由于识别来自横纹肌特异性蛋白肌联蛋白的不相关肽。这些患者表明，TCR工程化的T细胞可能具有严重且不容易预测的脱靶和器官特异性毒性，并强调需要改进方法来定义工程化TCR的特异性。（血。2013; 122（6）：863-871）
An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs. (Blood. 2013; 122(6):863-871)