MIG (CXCL9) chemokine gene therapy combines with antibody-cytokine fusion protein to suppress growth and dissemination of murine colon carcinoma.
MIG (CXCL9) chemokine gene therapy combines with antibody-cytokine fusion protein to suppress growth and dissemination of murine colon carcinoma.
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发表时间：
2001-12
期刊：
影响因子：
11.2
通讯作者：
J. Ruehlmann;Rong Xiang;A. Niethammer;Yi Ba;U. Pertl;C. Dolman;S. D. Gillies;Ralph A. Reisfeld
中科院分区：
文献类型：
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作者：
J. Ruehlmann;Rong Xiang;A. Niethammer;Yi Ba;U. Pertl;C. Dolman;S. D. Gillies;Ralph A. Reisfeld
诱导能够根除播散性肿瘤转移的CTL应答和建立持久的肿瘤保护性免疫仍然是癌症免疫治疗的主要目标。在这里，我们首次证明了通过重组抗体-IL-2融合蛋白（huKS 1/4-IL-2）靶向肿瘤微环境的白细胞介素2（IL-2）与鼠趋化因子CXCL 9（CXCL 9）的基因治疗的组合显著降低了s.c.在同基因BALB/c小鼠中CT 26-KSA结肠癌的实验性肺转移的肿瘤负荷和决定性抑制的扩散。这种联合疗法通过同时将IL-2和IL-4递送到肿瘤部位，从而实现T细胞的化学吸引以及它们的活化，显著延长了这些小鼠的寿命3-4倍。所获得的抗肿瘤作用主要由MHC I类抗原限制性CD 8（+）T细胞介导，并得到MHC II类抗原限制性CD 4（+）T淋巴细胞的帮助。此外，该趋化因子还在肿瘤血管系统中诱导血管生成抑制作用。总而言之，这种联合应用趋化因子基因治疗与肿瘤靶向细胞因子IL-2的方法为合理设计新型癌症免疫治疗模式提供了一种途径。
The induction of a CTL response capable of eradicating disseminated tumor metastases and the establishment of a persistent tumor-protective immunity remain major goals of cancer immunotherapy. Here, we demonstrate for the first time that the combination of interleukin 2 (IL-2) targeted to the tumor microenvironment by a recombinant antibody-IL-2 fusion protein (huKS1/4-IL-2) with gene therapy by the murine chemokine MIG (CXCL9) markedly reduced s.c. tumor burden and decisively suppressed dissemination of experimental lung metastases of CT26-KSA colon carcinoma in syngeneic BALB/c mice. This combined therapy significantly prolonged the life span of these mice 3-4-fold by concurrently delivering MIG and IL-2 to the tumor site and thereby achieving chemoattraction of T cells together with their activation. The antitumor effect obtained was mediated predominantly by MHC class I antigen-restricted CD8(+) T cells with help from MHC class II antigen-restricted CD4(+) T lymphocytes. In addition, the MIG chemokine also induced angiostatic effects in the tumor vasculature. Taken together, this combination of MIG chemokine gene therapy with tumor-targeted cytokine IL-2 provides an approach for the rational design of novel cancer immunotherapy modalities.