Rossig Claudia, Bär Annette, Pscherer Sibylle, Altvater Bianca, Pule Martin, Rooney Cliona M, Brenner Malcolm K, Jürgens Heribert, Vormoor Josef
Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.
J Immunother. 2006 Jan-Feb;29(1):21-31. doi: 10.1097/01.cji.0000175492.28723.d6.
Human T cells expressing tumor antigen-specific chimeric receptors fail to sustain their growth and activation in vivo, which greatly reduces their therapeutic value. The defective proliferative response to tumor cells in vitro can partly be overcome by concomitant CD28 costimulatory signaling. We investigated whether T-cell activation via chimeric receptors (chRec) can be further improved by ligand expression on antigen-presenting cells of B-cell origin. We generated Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) expressing a CD19-specific chRec. These CTLs are provided with native receptor stimulation by autologous EBV-transformed B-lymphoblastoid cell lines (LCLs) but exclusively with chRec (CD19-specific) stimulation by allogeneic, human leukocyte antigen (HLA)-mismatched CD19+ LCLs. CD19zeta-transduced EBV-specific CTLs specifically lysed both allogeneic EBV targets and CD19+ tumor cells through the chRec in a major histocompatibility complex-independent manner, while maintaining their ability to recognize autologous EBV targets through the native T-cell receptor. The transduced CTLs failed to proliferate in response to CD19+ tumor targets even in the presence of CD28 costimulatory signaling. By contrast, CD19 expressed on HLA-mismatched LCL-induced T-cell activation and long-term proliferation that essentially duplicated the result from native receptor stimulation with autologous LCLs, suggesting that a deficit of costimulatory molecules on target cells in addition to CD28 is indeed responsible for inadequate chRec-mediated T-cell function. Hence, effective tumor immunotherapy may be favored if engagement of the chRec on modified T cells is complemented by interaction with multiple costimulator molecules. The use of T cells with native specificity for EBV may be one means of attaining this objective.
表达肿瘤抗原特异性嵌合受体的人T细胞在体内无法维持其生长和激活，这大大降低了它们的治疗价值。体外对肿瘤细胞的增殖反应缺陷可通过同时存在的CD28共刺激信号部分克服。我们研究了通过嵌合受体（chRec）激活T细胞是否可以通过B细胞来源的抗原呈递细胞上的配体表达得到进一步改善。我们生成了表达CD19特异性chRec的爱泼斯坦-巴尔病毒（EBV）特异性细胞毒性T淋巴细胞（CTL）。这些CTL通过自体EBV转化的B淋巴母细胞系（LCL）获得天然受体刺激，但仅通过同种异体、人类白细胞抗原（HLA）不匹配的CD19+LCL获得chRec（CD19特异性）刺激。CD19ζ转导的EBV特异性CTL通过chRec以主要组织相容性复合体非依赖的方式特异性裂解同种异体EBV靶标和CD19+肿瘤细胞，同时保持其通过天然T细胞受体识别自体EBV靶标的能力。即使存在CD28共刺激信号，转导的CTL也未能对CD19+肿瘤靶标作出增殖反应。相比之下，HLA不匹配的LCL上表达的CD19诱导T细胞激活和长期增殖，其结果基本上与自体LCL的天然受体刺激结果相同，这表明除了CD28之外，靶细胞上共刺激分子的缺乏确实是chRec介导的T细胞功能不足的原因。因此，如果修饰T细胞上chRec的结合通过与多种共刺激分子的相互作用得到补充，可能有利于有效的肿瘤免疫治疗。使用对EBV具有天然特异性的T细胞可能是实现这一目标的一种手段。
