Improving Adoptive T Cell Therapy by Targeting and Controlling IL-12 Expression to the Tumor Environment
Improving Adoptive T Cell Therapy by Targeting and Controlling IL-12 Expression to the Tumor Environment
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DOI：
10.1038/mt.2010.313
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发表时间：
2011-04-01
影响因子：
12.4
通讯作者：
Morgan, Richard A.
中科院分区：
文献类型：
--
作者：
Zhang, Ling;Kerkar, Sid P.;Morgan, Richard A.
白细胞介素-12（IL-12）是一种重要的免疫刺激细胞因子，但其给药引起的全身毒性限制了其临床应用。在这项工作中，我们开发了一种策略，使用基因工程淋巴细胞选择性地将IL-12递送到肿瘤环境中。然而，外周血淋巴细胞（PBL）转导a.组成型表达IL-12的逆转录病毒载体由于细胞凋亡而不能在培养物中扩增。为了避免这个问题，设计了一种载体，其中IL-12的表达由含有活化T细胞核因子结合基序的复合启动子（NFAT. hIL 12. PA 2）指导。NFAT响应性启动子被激活，以在识别由工程化到相同淋巴细胞中的T细胞受体（TCR）介导的肿瘤特异性抗原后驱动IL-12表达。我们测试了诱导型IL-12载体在鼠黑素瘤模型中的体内功效。用NFAT-鼠IL 12（NFAT. PA 2）显著增强了大的已建立的B16黑素瘤的消退。值得注意的是，这种靶向和受控的IL-12治疗没有毒性。综上所述，我们的结果表明，使用NFAT. hIL 12. PA 2载体可能是增强过继性肿瘤免疫治疗的一种有前途的方法。
Interleukin-12 (IL-12) is an important immunostimulatory cytokine, yet its clinical application has been limited by the systemic toxicity associated with its administration. In this work, we developed a strategy to selectively deliver IL-12 to the tumor environment using genetically engineered lymphocytes. However, peripheral blood lymphocytes (PBLs) transduced with a.-retroviral vector, which constitutively expressed IL-12, failed to expand in culture due to apoptosis. To circumvent this problem, a vector was designed where IL-12 expression was directed by a composite promoter-containing binding motifs for nuclear factor of activated T-cells (NFAT.hIL12.PA2). The NFAT-responsive promoter was activated to drive IL-12 expression upon the recognition of tumor-specific antigen mediated by a T cell receptor (TCR) that was engineered into the same lymphocytes. We tested the efficacy of the inducible IL-12 vector in vivo in a murine melanoma model. Adoptive transfer of pmel-1 T cells genetically engineered with NFAT-murineIL12 (NFAT. mIL12.PA2) significantly enhanced regression of large established B16 melanoma. Notably, this targeted and controlled IL-12 treatment was without toxicity. Taken together, our results suggest that using the NFAT.hIL12. PA2 vector might be a promising approach to enhance adoptive cancer immunotherapy.