Targeted delivery of tumor necrosis factor-α to tumor vessels induces a therapeutic T cell-mediated immune response that protects the host against syngeneic tumors of different histologic origin
Targeted delivery of tumor necrosis factor-α to tumor vessels induces a therapeutic T cell-mediated immune response that protects the host against syngeneic tumors of different histologic origin
复制标题
DOI：
10.1158/1078-0432.ccr-05-2448
复制
发表时间：
2006-04-15
影响因子：
11.5
通讯作者：
Borsi, L
中科院分区：
文献类型：
--
作者：
Balza, E;Mortara, L;Borsi, L
目的：我们试图证明单次全身给予L19 mTNF α（由对纤连蛋白的癌胚ED-B结构域特异的scFv L19和肿瘤坏死因子α构成的融合蛋白，TNF α）与美法仑联合诱导荷瘤小鼠完全和持久的肿瘤根除，并触发特异性T细胞的产生，基于免疫应答，保护动物免受第二次肿瘤攻击，以及不同组织学来源的同源肿瘤细胞的攻击。实验设计和结果：L19 mTNF α联合美法仑治疗可诱导83%的WEHI-164纤维肉瘤BALB/c小鼠和33%的C51结肠癌动物的肿瘤完全消退。所有治愈的小鼠都拒绝了相同肿瘤细胞的攻击，并且在非常高比例的动物中，也拒绝了不同组织学来源的同源肿瘤细胞的攻击。在过继免疫转移实验中，来自肿瘤治愈小鼠的脾细胞保护未处理小鼠免受C51结肠癌和WEHI-164纤维肉瘤的侵害。在使用严重免疫抑制小鼠的过继免疫转移实验中也获得了类似的结果。使用耗尽的脾细胞进行的实验表明，T细胞在肿瘤排斥反应中发挥主要作用。结论：结果表明，mTNF α选择性靶向肿瘤增强了其免疫刺激特性，达到针对不同组织学无关的同基因肿瘤产生治疗性免疫反应的程度。这些发现预测了基于TNF α靶向递送至肿瘤血管系统的癌症患者的治疗方法。
Purpose: We sought to demonstrate that a single systemic administration of L19mTNF alpha (a fusion protein constituted by the scFv L19 specific for the oncofetal ED-B domain of fibronectin and tumor necrosis factor alpha, TNF alpha) in combination with melphalan induced complete and long-lasting tumor eradication in tumor-bearing mice and triggered the generation of a specific T cell-based immune response that protects the animals from a second tumor challenge, as well as from challenges with syngeneic tumor cells of different histologic origin.Experimental Design and Results: Treatment with L19mTNF alpha, in combination with melphalan, induced complete tumor regression in 83% of BALB/c mice with WEHI-164 fibrosarcoma and 33% of animals with C51 colon carcinoma. All cured mice rejected challenges with the same tumor cells and, in a very high percentage of animals, also rejected challenges with syngeneic tumor cells of different histologic origin. In adoptive immunity transfer experiments, the splenocytes from tumor-cured mice protected naive mice both from C51 colon carcinoma and from WEHI-164 fibrosarcoma. Similar results were also obtained in adoptive immunity transfer experiments using severely immunodepressed mice. Experiments using depleted splenocytes showed that T cells play a major role in tumor rejection.Conclusions:The results show that the selective targeting of mTNF alpha to the tumor enhances its immunostimulatory properties to the point of generating a therapeutic immune response against different histologically unrelated syngeneic tumors. These findings predicate treatment approaches for cancer patients based on the targeted delivery of TNF alpha to the tumor vasculature.