Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T-cells
Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T-cells
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DOI：
10.1002/pros.20608
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发表时间：
2007-07-01
期刊：
影响因子：
2.8
通讯作者：
Temme, Achim
中科院分区：
文献类型：
--
作者：
Morgenroth, Agnieszka;Cartellieri, Marc;Temme, Achim
背景资料。前列腺癌(PCA)微小残留病或晚期肿瘤的治疗选择仍然缺乏。过继转移通过基因工程多克隆获得的肿瘤特异性细胞毒性T细胞似乎是一种有前途的免疫治疗策略。在近几年发现的众多前列腺组织/肿瘤抗原中，前列腺癌干细胞抗原(PSCA)是一个很有吸引力的免疫治疗靶点。方法制备抗PSCA的单链抗体，构建识别PSCA的嵌合T细胞受体(TCR)。结果在Jurkat细胞中表达的α-PSCA-β2/CD3-Zeta-TCR融合蛋白在CD3-Zeta链的ITAM中发生磷酸化。当转导入小鼠细胞毒性T细胞系时，嵌合受体特异性地激活了对PSCA阳性肿瘤细胞的细胞毒作用。结论：我们开发了一种针对PSCA的功能性嵌合TCR，用于治疗前列腺癌。嵌合的α-PSCA-β2/CD3 Zeta-TCR现在可能被用来武装人类细胞毒性T细胞，为进一步研究PCa的临床治疗奠定基础。
BACKGROUND. Curative therapeutic options for minimal residual disease or advanced tumor stages in prostate cancer (PCa) are still missing. Adoptive transfer of cytotoxic T-cells that have been polyclonally rendered tumor-specific by genetic engineering appears to be a promising immunotherapeutic strategy. Among the numerous prostate tissue/tumor antigens identified during the last years, the "prostate stem cell antigen" (PSCA) is an attractive immunotherapeutic target. It is broadly expressed on the surface of primary PCa cells as well as on PCa metastases.METHODS. To generate a chimeric T-cell receptor (TCR) recognizing PSCA, a monoclonal anti-PSCA antibody was raised and a single-chain fragment (scFv) was prepared. The resulting anti-PSCA scFv 7F5 was fused to the beta 2 constant region derived from the beta-chain of a TCR and to the CD3 zeta-signaling domain.RESULTS. The chimeric alpha-PSCA-beta 2/CD3 zeta-TCR, expressed in Jurkat cells, was phosphorylated in the ITAMs of the CD3-zeta chain upon cross-linking by insolublized PSCA. When transduced into a mouse cytotoxic T-cell line, the chimeric receptor specifically activated cytotoxicity against PSCA-positive tumor cells.CONCLUSIONS. We developed a functional chimeric TCR against PSCA for treatment of PCa. The chimeric alpha-PSCA-beta 2/CD3 zeta-TCR might now be used for arming human cytotoxic T-cells for further studies towards a clinical treatment of PCa.