Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds.
Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds.
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DOI：
10.1634/stemcells.2008-0831
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发表时间：
2009-03
期刊：
影响因子：
--
通讯作者：
Alvarez-Vallina L
中科院分区：
文献类型：
--
作者：
Compte M;Cuesta AM;Sánchez-Martín D;Alonso-Camino V;Vicario JL;Sanz L;Alvarez-Vallina L
间充质干细胞(MSCs)因其易于扩增和转导而成为基因治疗的细胞载体。然而，MSCs表现出免疫调节和促血管生成的特性，这可能会对其在抗癌治疗中的使用构成风险。出于这个原因，我们寻找了一种策略，将MSCs限制在一个确定的位置，与临床应用兼容。转基因表达荧光素酶的人骨髓间充质干细胞(MSCluc)接种于人工合成的细胞外基质(SECM)支架(前哨支架)中，注射到免疫缺陷小鼠的皮下，通过体内生物发光成像评估，持续了40天以上。经修饰表达双特异性α癌胚抗原(αCEA)/αCD3Diabody(MSCdAb)的骨髓间充质干细胞种植于SECM支架(治疗性支架)中，可支持功能性Diabody在植入后至少6周内释放到可检测的水平。此外，当治疗性支架植入CEA阳性的人结肠癌移植瘤小鼠并随后转移人T淋巴细胞时，循环αCEA/αCD3Diabody激活T细胞并促进肿瘤细胞的溶解。与只接受MSCluc治疗的小鼠相比，MSCdAb治疗的小鼠的肿瘤生长速度显著减少。综上所述，我们在此首次报道，通过基因工程，人的MSCs可以分泌一种双特异性二倍体，种植在SECM支架中，并植入远离原发肿瘤的位置，从而诱导有效的抗肿瘤反应和肿瘤消退。
Mesenchymal stem cells (MSCs) are appealing as gene therapy cell vehicles given their ease of expansion and transduction. However, MSCs exhibit immunomodulatory and proangiogenic properties that may pose a risk in their use in anticancer therapy. For this reason, we looked for a strategy to confine MSCs to a determined location, compatible with a clinical application. Human MSCs genetically modified to express luciferase (MSCluc), seeded in a synthetic extracellular matrix (sECM) scaffold (sentinel scaffold) and injected subcutaneously in immunodeficient mice, persisted for more than 40 days, as assessed by bioluminescence imaging in vivo. MSCs modified to express a bispecific α-carcinoembryonic antigen (αCEA)/αCD3 diabody (MSCdAb) and seeded in an sECM scaffold (therapeutic scaffolds) supported the release of functional diabody into the bloodstream at detectable levels for at least 6 weeks after implantation. Furthermore, when therapeutic scaffolds were implanted into CEA-positive human colon cancer xenograft-bearing mice and human T lymphocytes were subsequently transferred, circulating αCEA/αCD3 diabody activated T cells and promoted tumor cell lysis. Reduction of tumor growth in MSCdAb-treated mice was statistically significant compared with animals that only received MSCluc. In summary, we report here for the first time that human MSCs genetically engineered to secrete a bispecific diabody, seeded in an sECM scaffold and implanted in a location distant from the primary tumor, induce an effective antitumor response and tumor regression.
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影响因子：
11.2
作者：
Nakamizo, A;Marini, F;Lang, FF
通讯作者：
Lang, FF
影响因子：
12.4
作者：
Chen, Xiancheng;Lin, Xiaojuan;Zhao, Xia
通讯作者：
Zhao, Xia
影响因子：
--
作者：
Liu, Yanchun;Shu, Xiao Zheng;Prestwich, Glenn D.
通讯作者：
Prestwich, Glenn D.
影响因子：
5.1
作者：
Eliopoulos, N;Al-Khaldi, A;Galipeau, J
通讯作者：
Galipeau, J
影响因子：
5.2
作者：
Lazennec, Gwendal;Jorgensen, Christian
通讯作者：
Jorgensen, Christian