Siteman Cancer Center and Departments of Medicine and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Blood. 2013 Aug 8;122(6):863-71. doi: 10.1182/blood-2013-03-490565. Epub 2013 Jun 14.
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.
癌症免疫疗法的一个障碍是，T 细胞受体 (TCRs) 与肿瘤中表达的抗原的亲和力通常较低。我们开始对表达亲和力增强的 TCR 的工程化 T 细胞进行临床试验，以针对 HLA-A*01 限制的 MAGE-A3 进行检测。针对骨髓瘤和黑色素瘤患者的 TCR 检测已启动开放性试验方案。前两名接受治疗的患者在 T 细胞输注后几天内发生心源性休克并死亡，这些事件是高亲和力 TCR 临床前研究无法预测的。尸检的大体发现显示严重的心肌损伤，组织病理学分析显示 T 细胞浸润。心脏尸检组织中未检测到 MAGE-A3 表达。在两名患者中均证实体内工程化 T 细胞的大量增殖。从诱导多能干细胞生成的搏动心肌细胞培养物触发 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无关肽。这些患者表明，TCR 工程化 T 细胞可能具有严重且不易预测的脱靶和器官特异性毒性，并强调需要改进方法来确定工程化 TCR 的特异性。
