Gade Terence P F, Hassen Waleed, Santos Elmer, Gunset Gertrude, Saudemont Aurore, Gong Michael C, Brentjens Renier, Zhong Xiao-Song, Stephan Matthias, Stefanski Jolanta, Lyddane Clay, Osborne Joseph R, Buchanan Ian M, Hall Simon J, Heston Warren D, Rivière Isabelle, Larson Steven M, Koutcher Jason A, Sadelain Michel
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Cancer Res. 2005 Oct 1;65(19):9080-8. doi: 10.1158/0008-5472.CAN-05-0436.
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 CD3zeta 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 1 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.
抗原受体的基因转移是快速产生肿瘤特异性T淋巴细胞的有效方法。与生理性T细胞受体不同，嵌合抗原受体（CAR）包含免疫球蛋白可变区或受体配体作为其抗原识别部分，从而使T细胞在缺乏人类白细胞抗原表达的情况下能够识别肿瘤抗原。包含CD3ζ链作为其激活域的CAR在体外可诱导T细胞增殖，但存活时间有限。基因靶向T细胞在体内发挥功能的要求尚不太清楚。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是一种在前列腺癌细胞和各种实体瘤的新生血管中表达的抗原。在患有已建立的前列腺腺癌的小鼠中，使用血清前列腺分泌抗原、磁共振、计算机断层扫描和生物发光成像来评估体内特异性和抗肿瘤活性，以研究对治疗的反应。在原位、皮下和肺部三种肿瘤模型中，我们表明靶向PSMA的T细胞可有效消除前列腺癌。肿瘤根除与体内效应细胞与肿瘤细胞的比例直接相关。连续成像进一步显示，T细胞必须存活至少1周才能诱导持久缓解。在小鼠环境中异种肿瘤的根除表明，过继转移的T细胞在体内发挥功能并不绝对需要共刺激。因此，这些结果为开展I期临床研究以评估转移性前列腺癌患者中靶向PSMA的T细胞提供了有力的理论依据。
