Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen
Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen
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DOI：
10.1182/blood-2009-03-211714
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发表时间：
2009-07-16
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：
Johnson, Laura A.;Morgan, Richard A.;Rosenberg, Steven A.
使用基因工程淋巴细胞进行人类癌症的基因治疗依赖于具有抗肿瘤活性的高反应性T细胞受体(TCR)的鉴定。我们免疫转基因小鼠，并对人类淋巴细胞进行高通量筛选，以产生对黑色素瘤/黑素细胞抗原高度反应的TCR。编码这些TCR的基因被工程化为逆转录病毒载体，并用于转导36例转移性黑色素瘤患者的自体外周淋巴细胞。转导的患者淋巴细胞体外扩增后为CD45RA(-)和CD45RO(+)。持续细胞输注后表现为CD45RA(+)和CD45RO(-)表型。基因工程细胞在治疗1个月后在所有患者的血液中持续保持高水平，与无反应者相比，对患者有更高的体外抗肿瘤反应。目的接受人或小鼠TCR的患者中，肿瘤消退率分别为30%和19%。然而，患者的皮肤、眼睛和耳朵中的正常黑素细胞遭到破坏，有时需要局部应用类固醇来治疗葡萄膜炎和听力损失。因此，表达高反应性TCR的T细胞介导人类癌症的消退，并靶向全身罕见的含有同源抗原的细胞，这一发现对癌症的基因治疗具有重要意义。这项试验在www.Clinicaltrials.gov上注册为NCI-07-C-0174和NCI-07-C-0175。(血。2009年；114：-546)
Gene therapy of human cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/melanocyte antigens. Genes encoding these TCRs were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA(-) and CD45RO(+) after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA(+) and CD45RO(-) phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. Objective cancer regressions were seen in 30% and 19% of patients who received the human or mouse TCR, respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye, and ear, and sometimes required local steroid administration to treat uveitis and hearing loss. Thus, T cells expressing highly reactive TCRs mediate cancer regression in humans and target rare cognate -antigen-containing cells throughout the body, a finding with important implications for the gene therapy of cancer. This trial was registered at www.ClinicalTrials.gov as NCI-07-C-0174 and NCI-07-C-0175. (Blood. 2009; 114: 535-546)