Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts.
Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts.
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DOI：
10.4049/jimmunol.155.3.1393
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发表时间：
1995-08
影响因子：
4.4
通讯作者：
Laurence Zitvogel;Hideaki Tahara;Paul D. Robbins;W. Storkus;Martha R. Clarke;M. Nalesnik;M. T. Lotze
中科院分区：
文献类型：
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作者：
Laurence Zitvogel;Hideaki Tahara;Paul D. Robbins;W. Storkus;Martha R. Clarke;M. Nalesnik;M. T. Lotze
IL-12是由巨噬细胞、促分裂原刺激或EBV感染的B淋巴细胞、角质形成细胞和可能的树突细胞产生的异二聚体细胞因子，在体外和体内具有重要的免疫调节功能。它直接刺激活化的NK和T细胞产生高水平的IFN-γ，增强它们的细胞溶解活性，并促进Th 1细胞以及IL-2活化的B细胞的成熟。我们已经使用经工程改造以分泌高水平IL-12的自体或同种异体成纤维细胞测试了IL-12的旁分泌递送以治疗已建立的肿瘤。在建立的（第8天）MCA 207肉瘤的部位注射IL-12工程化的成纤维细胞可以以剂量依赖性方式有效地消除或抑制肿瘤生长，需要递送> 150 ng/kg/剂量的生物活性IL-12。每周接种3周也可用于有效治疗位于对侧腹皮内的第4天肉瘤（使用自体成纤维细胞的80%保护），产生长期保护性抗肿瘤免疫。在免疫原性较低的肿瘤（MCA 102，MC 38）中，通过成纤维细胞递送IL-12和全身给予低剂量IL-2后，7天建立的肺转移可显著减少（p = 0.001）。组织学结果包括第21天消退肉瘤中的CD 4+和CD 8 + T效应细胞和巨噬细胞的混合浸润。在第41天局部原位注射的MCA 207肉瘤中，观察到类似的发现。在接受IL-12工程化成纤维细胞重复接种的小鼠中，在肝、脾或肺中未观察到淋巴样增生或组织坏死。每周重复治疗期间监测的肝肾功能检查结果均在正常范围内。因此，IL-12工程化的成纤维细胞似乎在这三种肿瘤模型中充当递送IL-12的安全且有效的手段。
IL-12 is a heterodimeric cytokine produced by macrophages, mitogen stimulated- or EBV infected-B lymphocytes, keratinocytes, and probably dendritic cells, with important immunoregulatory functions in vitro and in vivo. It directly stimulates activated NK and T cells to produce high levels of IFN-gamma, enhances their cytolytic activity, and promotes maturation of Th1 cells as well as IL-2-activated B cells. We have tested paracrine delivery of IL-12 using autologous or allogeneic fibroblasts engineered to secrete high levels of IL-12 to treat established tumors. Injection of IL-12-engineered fibroblasts at the site of an established (day 8) MCA207 sarcoma could efficiently eliminate or suppress tumor growth in a dose-dependent manner, requiring delivery of > 150 ng/kg/dose of bioactive IL-12. Weekly inoculations for 3 wk could also be used to effectively treat a day 4 sarcoma located intradermally in the opposite flank (80% protection using autologous fibroblasts), resulting in long-term protective antitumor immunity. In less immunogenic tumors (MCA102, MC38), 7-day established lung metastases could be significantly reduced (p = 0.001) following IL-12 delivery by fibroblasts and systemic administration of low doses of IL-2. Histologic findings included a mixed infiltrate of CD4+ and CD8+ T effectors and macrophages in the regressing sarcoma on day 21. In a day 41 MCA207 sarcoma locally injected in situ, similar findings were observed. No lymphoid hyperplasia or tissue necrosis were noted in liver, spleen, or lungs in mice receiving repeated inocula of IL-12-engineered fibroblasts. Tests of liver and renal function monitored during the repetitive weekly treatments were within the normal range. IL-12-engineered fibroblasts thus seem to serve as a safe and efficient means to deliver IL-12 in these three tumor models.