Balza Enrica, Mortara Lorenzo, Sassi Francesca, Monteghirfo Stefano, Carnemolla Barbara, Castellani Patrizia, Neri Dario, Accolla Roberto S, Zardi Luciano, Borsi Laura
Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro, Unit of Innovative Therapies, Istituto Giannina Gaslini, Centro Biotecnologie Avanzate, Genoa, Italy.
Clin Cancer Res. 2006 Apr 15;12(8):2575-82. doi: 10.1158/1078-0432.CCR-05-2448.
We sought to demonstrate that a single systemic administration of L19mTNFalpha (a fusion protein constituted by the scFv L19 specific for the oncofetal ED-B domain of fibronectin and tumor necrosis factor alpha, TNFalpha) 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.
Treatment with L19mTNFalpha, 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.
The results show that the selective targeting of mTNFalpha 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 TNFalpha to the tumor vasculature.
我们试图证明，单次全身给予L19mTNFα（一种由对纤连蛋白癌胚ED-B结构域具有特异性的单链抗体片段L19和肿瘤坏死因子α，即TNFα组成的融合蛋白）联合美法仑可在荷瘤小鼠中诱导完全且持久的肿瘤根除，并引发基于特异性T细胞的免疫反应，从而保护动物免受第二次肿瘤攻击，以及来自不同组织学来源的同基因肿瘤细胞的攻击。
L19mTNFα联合美法仑治疗使83%患有WEHI-164纤维肉瘤的BALB/c小鼠和33%患有C51结肠癌的动物出现完全肿瘤消退。所有治愈的小鼠均能抵抗相同肿瘤细胞的攻击，并且在很高比例的动物中，也能抵抗来自不同组织学来源的同基因肿瘤细胞的攻击。在过继免疫转移实验中，来自肿瘤治愈小鼠的脾细胞保护了未接触过肿瘤的小鼠免受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结果。使用去除特定细胞成分的脾细胞进行的实验表明，T细胞在肿瘤排斥中起主要作用。
结果表明，将mTNFα选择性靶向肿瘤可增强其免疫刺激特性，从而产生针对不同组织学无关的同基因肿瘤的治疗性免疫反应。这些发现为基于将TNFα靶向递送至肿瘤脉管系统的癌症患者治疗方法提供了依据。
