Combining tumor-targeted superantigens with interferon-alpha results in synergistic anti-tumor effects
Combining tumor-targeted superantigens with interferon-alpha results in synergistic anti-tumor effects
复制标题
DOI：
10.1016/j.intimp.2007.11.006
复制
发表时间：
2008-03-01
影响因子：
5.6
通讯作者：
Hedlund, Gunnar
中科院分区：
文献类型：
--
作者：
Sundstedt, Anette;Celander, Mona;Hedlund, Gunnar
在这项研究中，我们探讨了通过与干扰素-α（IFN-α）联合治疗来提高肿瘤靶向超抗原（TTS）抗肿瘤效力的可能性。TTS利用与抗肿瘤Fab片段融合的超抗原葡萄球菌肠毒素A（SEA）的强大T细胞活化特性来靶向这种针对肿瘤细胞的T细胞活性。TTS融合蛋白在许多实验肿瘤模型中显示出抗肿瘤功效，包括用C215单克隆抗体识别的人莫尔相关抗原转染的B16小鼠黑素瘤。IFN-α被批准用于治疗实体瘤如肾细胞癌和恶性黑色素瘤，并发挥免疫调节作用，这使其成为联合收割机与免疫疗法组合对抗癌症的合适候选物。在这里，我们报告了每天给予IFN-α（20 000 U i. p.）增强并维持TTS C215 Fab-SEA（10 μ g i. v.）在C57 B1/6小鼠中，如通过增加和延长的细胞介导的对肿瘤细胞的离体细胞毒性以及通过增加的血清IFN-γ水平所反映的。与单一疗法相比，C215 Fab-SEA与IFN-α协同减少携带B16-C215黑素瘤的小鼠中的肺肿瘤数量。在长期肿瘤存活实验中，组合治疗的延长的中值存活时间分别是C215 Fab-SEA和IFN-α单一治疗的延长的中值存活时间的3.5和7.7倍。因此，联合治疗引起协同抗肿瘤作用，如通过肺肿瘤的数量和显著延长的生存期所测量的。增强的治疗效果与CD 8和穿孔素表达的肿瘤浸润细胞的显著和持续增加相关。这些结果表明TTS与IFN-α组合用于人类癌症治疗的显著潜力。(c)2007 Elsevier B. V.保留所有权利。
In this study we explored the possibility of improving the anti-tumor potency of tumor-targeted superantigens (TTS) by combination treatment with interferon-alpha (IFN-alpha). TTS utilizes the powerful T cell activating property of the superantigen staphylococcal enterotoxin A (SEA) in fusion with an anti-tumor Fab-fragment to target this T cell activity against tumor cells. TTS fusion proteins have shown anti-tumor efficacy in a number of experimental tumor models including the B16 mouse melanoma transfected with a human tu mor- associated antigen recognized by the C215 monoclonal antibody. IFN-alpha is approved for the treatment of solid tumors such as renal cell carcinoma and malignant melanoma and exerts immunomodulatory effects, which make it an appropriate candidate to combine with immunotherapy against cancer. Here we report that daily administration of IFN-alpha (20 000 U i.p.) enhances and sustains CD8(+) T cell activation induced by the TTS C215Fab-SEA (10 mu g i.v.) in C57Bl/6 mice, as reflected by increased and prolonged cell-mediated cytotoxicity against tumor cells ex vivo as welt as by augmented serum IFN-gamma levels. C215Fab-SEA synergized with IFN-alpha in reducing the number of lung tumors in B16-C215 melanoma bearing mice as compared to mono therapy. In a long term tumor survival experiment, the prolonged median survival time of the combination treatment was 3.5 and 7.7 times the prolonged median survival times of C215Fab-SEA and IFN-alpha monotherapies, respectively. Hence, the combination treatment provoked synergistic anti-tumor effects as measured by the number of lung tumors and markedly prolonged survival. The enhanced therapeutic efficacy correlated with a striking and sustained increase of CD8- and perforin-expressing tumor-infiltrating cells. These results suggest significant potential of combining TTS with IFN-alpha for human cancer therapy. (c) 2007 Elsevier B.V. All rights reserved.