Targeted elimination of prostate cancer by genetically directed human T lymphocytes
Targeted elimination of prostate cancer by genetically directed human T lymphocytes
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DOI：
10.1158/0008-5472.can-05-0436
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发表时间：
2005-10-01
期刊：
影响因子：
11.2
通讯作者：
Sadelain, M
中科院分区：
文献类型：
--
作者：
Gade, TPF;Hassen, W;Sadelain, M
抗原受体的遗传转移是快速产生肿瘤特异性T淋巴细胞的有力途径。与生理性T细胞受体不同，嵌合抗原受体（汽车）包含免疫球蛋白可变区或受体配体作为其抗原识别部分，从而允许T细胞在不存在人白细胞抗原表达的情况下识别肿瘤抗原。包含CD3 ζ链作为其活化结构域的汽车在体外诱导T细胞增殖，但存活有限。遗传靶向T细胞在体内发挥作用的要求还不太清楚。因此，我们建立了动物模型，以评估靶向前列腺特异性膜抗原（PSMA）的人外周血T淋巴细胞的治疗效果，PSMA是前列腺癌细胞和各种实体瘤的新血管中表达的抗原。在体内特异性和抗肿瘤活性进行了评估，在小鼠建立的前列腺癌，使用血清前列腺分泌抗原，磁共振，计算机断层扫描，生物发光成像，以研究对治疗的反应。在三种肿瘤模型中，原位，皮下，和肺部，我们表明PSMA靶向T细胞有效地消除了前列腺癌。肿瘤根除与体内效应细胞与肿瘤细胞的比例成正比。连续成像进一步揭示T细胞必须存活至少1周以诱导持久缓解。异种肿瘤在小鼠环境中的根除表明过继转移的T细胞并不绝对需要体内共刺激来发挥功能。因此，这些结果为进行I期临床研究以评估转移性前列腺癌患者中的PSMA靶向T细胞提供了强有力的理论基础。
The genetic transfer of antigen receptors is a powerful approach to rapidly generate tumor-specific T lymphocytes. Unlike the physiologic T-cell receptor, chimeric antigen receptors (CARs) encompass immunoglobulin variable regions or receptor ligands as their antigen recognition moiety, thus permitting T cells to recognize tumor antigens in the absence of human leukocyte antigen expression. CARs encompassing the CD3 zeta chain as their activating domain induce T-cell proliferation in vitro, but limited survival. The requirements for genetically targeted T cells to function in vivo are less well understood. We have, therefore, established animal models to assess the therapeutic efficacy of human peripheral blood T lymphocytes targeted to prostate-specific membrane antigen (PSMA), an antigen expressed in prostate cancer cells and the neovasculature of various solid tumors. In vivo specificity and antitumor activity were assessed in mice bearing established prostate adenocarcinomas, using serum prostate-secreted antigen, magnetic resonance, computed tomography, and bioluminescence imaging to investigate the response to therapy. In three tumor models, orthotopic, s.c., and pulmonary, we show that PSMA-targeted T cells effectively eliminate prostate cancer. Tumor eradication was directly proportional to the in vivo effector-to-tumor cell ratio. Serial imaging further reveals that the T cells must survive for at least I week to induce durable remissions. The eradication of xenogeneic tumors in a murine environment shows that the adoptively transferred T cells do not absolutely require in vivo costimulation to function. These results thus provide a strong rationale for undertaking phase I clinical studies to assess PSMA-targeted T cells in patients with metastatic prostate cancer.