Sheen Aali J, Irlam Joely, Kirillova Natalia, Guest Ryan D, Sherlock David J, Hawkins Robert E, Gilham David E
Cancer Research United Kingdom, Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, United Kingdom.
Dis Colon Rectum. 2003 Jun;46(6):793-804. doi: 10.1007/s10350-004-6659-1.
The overall aim of this study was to develop a novel treatment for colorectal cancer based on the use of gene therapy. Genetic modification of T lymphocytes has been used to specifically target and kill tumor cell lines directly. To test the efficacy of this method with clinically relevant materials, this study investigated the potential of T lymphocytes derived from patients with advanced colorectal disease to target autologous primary tumor material. METHODS T lymphocytes isolated preoperatively were modified genetically with recombinant retroviruses encoding CD3zeta-based chimeric immune receptors and were tested for functional activity against freshly isolated autologous tumor cells harvested from hepatic colorectal metastases.
Patient-derived T cells were successfully transduced, and chimeric immune receptor expression was confirmed. Carcinoembryonic antigen expression on freshly isolated colorectal tumor cells was also demonstrated by molecular and immunohistochemical techniques. T cells expressing the anticarcinoembryonic antigen receptor were specifically activated by coculture with disaggregated or intact, diced tumor, whereas control non-carcinoembryonic antigen-targeted T-cell populations failed to activate.
These results indicate that gene-targeted primary T lymphocytes depict specific functional activity against autologous colorectal tumor cells. This evidence indicates that chimeric immune receptor-expressing T cells may be able to circumvent the mechanisms used by tumor cells to avoid immune cell activity in vivo. This study emphasizes the potential of this approach as a therapy for carcinoembryonic antigen-expressing primary colorectal tumor and its metastases.
本研究的总体目标是基于基因疗法开发一种新型的结直肠癌治疗方法。对T淋巴细胞进行基因改造已被用于直接特异性靶向并杀死肿瘤细胞系。为了用临床相关材料测试该方法的疗效，本研究调查了晚期结直肠疾病患者来源的T淋巴细胞靶向自体原发性肿瘤材料的潜力。方法：术前分离的T淋巴细胞用编码基于CD3ζ的嵌合免疫受体的重组逆转录病毒进行基因改造，并测试其对从肝结直肠转移灶收获的新鲜分离的自体肿瘤细胞的功能活性。
成功转导了患者来源的T细胞，并证实了嵌合免疫受体的表达。通过分子和免疫组织化学技术也证实了新鲜分离的结直肠肿瘤细胞上癌胚抗原的表达。表达抗癌胚抗原受体的T细胞通过与解离的或完整的、切碎的肿瘤细胞共培养而被特异性激活，而对照的非癌胚抗原靶向T细胞群体未能被激活。
这些结果表明，基因靶向的原代T淋巴细胞对自体结直肠肿瘤细胞具有特异性功能活性。这一证据表明，表达嵌合免疫受体的T细胞可能能够规避肿瘤细胞在体内逃避免疫细胞活性所采用的机制。本研究强调了这种方法作为治疗表达癌胚抗原的原发性结直肠癌及其转移灶的潜在价值。
