Niederman Thomas M J, Ghogawala Zoher, Carter Bob S, Tompkins Hillary S, Russell Margaret M, Mulligan Richard C
Department of Genetics, Harvard Medical School, Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2002 May 14;99(10):7009-14. doi: 10.1073/pnas.092562399. Epub 2002 May 7.
The demonstration that angiogenesis is required for the growth of solid tumors has fueled an intense interest in the development of new therapeutic strategies that target the tumor vasculature. Here we report the development of an immune-based antiangiogenic strategy that is based on the generation of T lymphocytes that possess a killing specificity for cells expressing vascular endothelial growth factor receptors (VEGFRs). To target VEGFR-expressing cells, recombinant retroviral vectors were generated that encoded a chimeric T cell receptor comprised of VEGF sequences linked to intracellular signaling sequences derived from the zeta chain of the T cell receptor. After transduction of primary murine CD8 lymphocytes by such vectors, the transduced cells were shown to possess an efficient killing specificity for cells expressing the VEGF receptor, Flk-1, as measured by in vitro cytotoxicity assays. After adoptive transfer into tumor-bearing mice, the genetically modified cytotoxic T lymphocytes strongly inhibited the growth of a variety of syngeneic murine tumors and human tumor xenografts. An increased effect on in vivo tumor growth inhibition was seen when this therapy was combined with the systemic administration of TNP-470, a conventional angiogenesis inhibitor. The utilization of the immune system to target angiogenic markers expressed on tumor vasculature may prove to be a powerful means for controlling tumor growth.
实体瘤生长需要血管生成这一事实激发了人们对开发针对肿瘤血管系统的新治疗策略的浓厚兴趣。在此，我们报告一种基于免疫的抗血管生成策略的开发，该策略基于产生对表达血管内皮生长因子受体（VEGFRs）的细胞具有杀伤特异性的T淋巴细胞。为了靶向表达VEGFR的细胞，构建了重组逆转录病毒载体，其编码一种嵌合T细胞受体，该受体由与源自T细胞受体ζ链的细胞内信号序列相连的VEGF序列组成。用此类载体转导原代小鼠CD8淋巴细胞后，通过体外细胞毒性试验测定，转导后的细胞对表达VEGF受体Flk-1的细胞具有高效杀伤特异性。将基因改造的细胞毒性T淋巴细胞过继转移到荷瘤小鼠体内后，它们强烈抑制了多种同基因小鼠肿瘤和人肿瘤异种移植物的生长。当这种疗法与传统血管生成抑制剂TNP-470全身给药联合使用时，对体内肿瘤生长抑制的效果增强。利用免疫系统靶向肿瘤血管系统上表达的血管生成标志物可能被证明是控制肿瘤生长的有力手段。
