Controlled gene delivery can enhance therapeutic outcome for cancer immune therapy for melanoma.
Controlled gene delivery can enhance therapeutic outcome for cancer immune therapy for melanoma.
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DOI：
10.2174/1566523214666141121111630
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发表时间：
2015
影响因子：
3.6
通讯作者：
Heller R
中科院分区：
文献类型：
--
作者：
Shirley SA;Lundberg CG;Li F;Burcus N;Heller R
有效的递送仍然是基因治疗发展的主要障碍。虽然技术进步改善了一般的给药方式，但为了达到治疗效果，仍然需要控制给药方式。基因电转移（GET）可用于实现这一目标。仔细选择用于递送的参数，如振幅、持续时间和脉冲数量以及质粒结构，可以进行操作，以达到适当的局部表达水平。在临床前和临床研究中，我们已经证明，通过电转移将治疗性细胞因子白介素12 （IL-12）直接输送到肿瘤中，可以产生局部和全身的抗肿瘤作用。使用该模型，我们假设使用GET调节局部基因表达可以影响治疗结果。为了验证这一点，我们使用了多种GET协议和质粒来实现不同水平的局部IL-12表达。我们发现高局部基因表达并没有带来更好的治疗结果。这表明基因表达的水平和可能的持续时间在介导宿主对黑色素瘤的免疫反应中很重要。这些数据还强调了在选择GET的参数时考虑治疗的预期免疫结果的重要性。
Effective delivery still remains a major hurdle in the development of gene based therapies. While technological advances have occurred that have improved delivery in general, there is still a need for controlled delivery in order to achieve therapeutic effects. Gene electrotransfer (GET) can be utilized to accomplish this. Careful selection of parameters used for delivery such as amplitude, duration and number of pulses as well as plasmid construct can be manipulated in order to achieve appropriate levels of local expression. Previously we have shown that direct delivery of the therapeutic cytokine, interleukin 12 (IL-12), to tumors using electrotransfer can generate local and systemic anti-tumor effects in pre-clinical and clinical studies. Using this model we hypothesized that modulating local gene expression using GET can affect therapeutic outcome. To test this, we used multiple GET protocols and plasmids to achieve varying levels of local IL-12 expression. We found that high local gene expression did not give rise to a better therapeutic outcome. This suggests the level and possibly the duration of gene expression are important in mediating the host immune response against melanoma. These data also emphasize the importance of considering the desired immune outcome of the therapy when selecting parameters for GET.