Electrotransfer of IL-15/IL-15Rα Complex for the Treatment of Established Melanoma.
Electrotransfer of IL-15/IL-15Rα Complex for the Treatment of Established Melanoma.
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IL-15/IL-15Rα复合物的电转移用于治疗已建立的黑色素瘤。
DOI：
10.3390/cancers12103072
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发表时间：
2020-10-21
期刊：
影响因子：
5.2
通讯作者：
Heller R
中科院分区：
文献类型：
--
作者：
Shirley SA;Lundberg CG;Heller R
通过施用免疫调节剂如细胞因子来刺激免疫系统具有成为有效抗癌疗法的潜力。获得正确的剂量是关于最小化毒性和获得期望效果的重要方面。降低这种类型的治疗的毒性的方法是通过使用表达一种或多种这些抗癌剂的基因的DNA来代替高剂量重组蛋白注射。在本研究中，我们评估了白细胞介素-15及其受体在小鼠黑色素瘤模型中以质粒DNA形式的递送。我们利用一种递送方法，其可以以导致产生所需表达水平并诱导有效的抗肿瘤应答以及免疫记忆应答的方式递送质粒DNA。基因电转移（GET）是一种安全、可靠、有效的将质粒DNA（pDNA）导入实体瘤的方法。GET先前已用于向小鼠黑素瘤递送白细胞介素-15（IL-15），导致长期肿瘤消退和一定百分比的治疗动物在攻击后存活。为了增强这种作用，我们评估了调节IL-15的表达水平并共表达其受体IL-15 R α。在第0、4和7天，使用GET将编码IL-15和IL-15 R α的质粒递送至建立的B16.F10肿瘤。使用产生不同表达谱的两种递送方案。然后用B16.F10细胞在相反侧腹攻击无肿瘤50天的小鼠，并监测另外50天。IL-15的表达量和IL-15 R α的存在与否对肿瘤的消退和长期生存没有显著影响。然而，在攻击后，低水平的IL-15更具保护性，并导致抗肿瘤细胞因子如IFN-γ和MIP-1β的产生增加，以及浸润肿瘤的CD 11b+和CD 3e+细胞的量增加。虽然具有高水平IL-15的小鼠显示出CD 11b+和CD 3e+细胞浸润，但在其他处理组中不存在大量NK细胞。我们可以得出结论，GET后肿瘤中表达的IL-15水平是治疗结果的重要决定因素，这一发现将有助于我们微调这种类型的治疗。
The stimulation of the immune system through the administration of immunomodulatory agents such as cytokines has the potential to be an effective anti-cancer therapy. Obtaining the correct dose is an important aspect with respect to minimizing toxicity and obtaining the desired effect. A method to decrease the toxicity of this type of treatment is to replace the high-dose recombinant protein injections by using DNA expressing genes for one or more of these anti-cancer agents. In this current study, we have evaluated the delivery of interleukin-15 and its receptor in the form of plasmid DNA in a mouse melanoma model. We utilize a delivery approach that can deliver plasmid DNA in a manner that results in the desired level of expression being produced and induces a potent anti-tumor response as well as an immune memory response. Gene electrotransfer (GET) is a safe, reliable, and effective method of delivering plasmid DNA (pDNA) to solid tumors. GET has been previously used to deliver interleukin-15 (IL-15) to mouse melanoma, resulting in long-term tumor regression and the survival of a percentage of treated animals after challenge. To enhance this effect, we evaluated modulating the expression levels of IL-15 and co-expressing its receptor, IL-15Rα. GET was used to deliver plasmids encoding IL-15 and IL-15Rα to established B16.F10 tumors on days 0, 4, and 7. Two delivery protocols that yielded different expression profiles were utilized. Mice that were tumor-free for 50 days were then challenged with B16.F10 cells on the opposite flank and monitored for an additional 50 days. The amount of IL-15 expressed and the presence or absence of IL-15Rα in the treated tumors did not significantly affect the tumor regression and long-term survival. Upon challenge, however, low levels of IL-15 were more protective and resulted in a greater production of anti-tumor cytokines such as IFN-γ and MIP-1β and a greater amount of CD11b+ and CD3e+ cells infiltrating tumors. While mice with high levels of IL-15 showed CD11b+ and CD3e+ cell infiltrate, there was a substantial presence of NK cells that was absent in other treated groups. We can conclude that the level of IL-15 expressed in tumors after GET is an important determinant of the therapeutic outcome, a finding that will help us finetune this type of therapy.
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影响因子：
11.5
作者：
Bhatia, Shailender;Longino, Natalie V.;Miller, Natalie J.;Kulikauskas, Rima;Iyer, Jayasri G.;Ibrani, Dafina;Blom, Astrid;Byrd, David R.;Parvathaneni, Upendra;Twitty, Christopher G.;Campbell, Jean S.;Le, Mai H.;Gargosky, Sharron;Pierce, Robert H.;Heller, Richard;Daud, Adil I.;Nghiem, Paul
通讯作者：
Nghiem, Paul
影响因子：
2.3
作者：
Conlon, Kevin C.;Miljkovic, Milos D.;Waldmann, Thomas A.
通讯作者：
Waldmann, Thomas A.
影响因子：
32.4
作者：
Mortier, Erwan;Advincula, Rommel;Ma, Averil
通讯作者：
Ma, Averil
影响因子：
11.4
作者：
GIRI, JG;KUMAKI, S;ANDERSON, DM
通讯作者：
ANDERSON, DM
影响因子：
12.4
作者：
Lucas, ML;Heller, L;Heller, R
通讯作者：
Heller, R