Therapeutic Breast Reconstruction Using Gene Therapy-Delivered IFNγ Immunotherapy.
Therapeutic Breast Reconstruction Using Gene Therapy-Delivered IFNγ Immunotherapy.
复制标题
使用基因疗法提供的 IFNγ 免疫疗法进行治疗性乳房重建。
DOI：
10.1158/1535-7163.mct-19-0315
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发表时间：
2020
影响因子：
5.7
通讯作者：
Gurtner,GeoffreyC
中科院分区：
文献类型：
--
作者：
Davis,ChristopherR;Than,PeterA;Khong,SachaML;Rodrigues,Melanie;Findlay,MichaelW;Navarrete,DanielJ;Ghali,Shadi;Vaidya,JayantS;Gurtner,GeoffreyC
乳房切除术后，乳房再造越来越多地使用自体组织进行，目的是提高生活质量。在此过程中，自体组织被切除，重新定位，并在摘除的乳房部位使用微血管扩张术重新附着。在没有任何系统暴露于载体的情况下，组织可以进行遗传修饰的时期。这样的通路是否允许使用组织瓣作为载体来递送治疗剂？这样的递送可能比全身治疗更有针对性和肿瘤学效率，并且避免全身并发症。细胞因子IFNγ具有抗肿瘤作用，通过基因治疗将IFN γ基因局部递送到用于乳房再造的自体组织中，然后释放IFNγ并发挥抗肿瘤作用，可以避免全身毒性。在使用MADB-106-Luc和MAD-MB-231-Luc乳腺癌细胞的局部区域复发（LRR）的大鼠模型中，用编码IFNγ的腺相关病毒载体体内转导自体组织。与假手术组相比，“治疗性重建”组在LRR部位释放IFNγ并消除癌细胞，显著降低肿瘤负荷，并提高生存率（P<0.05）。从机制上讲，局部IFNγ免疫疗法刺激M1巨噬细胞在修饰的肿瘤环境的区域范围内靶向癌细胞。利用自体组织的体外基因治疗的“治疗性乳房重建”概念为乳腺癌的免疫治疗提供了一种新的应用，具有重建消融性缺损和提供局部辅助免疫治疗的双重治疗效果。
After mastectomy, breast reconstruction is increasingly performed using autologous tissue with the aim of improving quality of life. During this procedure, autologous tissue is excised, relocated, and reattached using microvascular anastomoses at the site of the extirpated breast. The period during which the tissue isex vivomay allow genetic modification without any systemic exposure to the vector. Could such access permit delivery of therapeutic agents using the tissue flap as a vehicle? Such delivery may be more targeted and oncologically efficient than systemic therapy, and avoid systemic complications. The cytokine IFNγ has antitumor effects, and systemic toxicity could be circumvented by localized delivery of theIFNγgene via gene therapy to autologous tissue used for breast reconstruction, which then releases IFNγ and exerts antitumor effects. In a rat model of loco-regional recurrence (LRR) with MADB-106-Luc and MAD-MB-231-Luc breast cancer cells, autologous tissue was transducedex vivowith an adeno-associated viral vector encoding IFNγ. The “Therapeutic Reconstruction” released IFNγ at the LRR site and eliminated cancer cells, significantly decreased tumor burden, and increased survival compared with sham reconstruction (P<0.05). Mechanistically, localized IFNγ immunotherapy stimulated M1 macrophages to target cancer cells within the regional confines of the modified tumor environment. This concept of “Therapeutic Breast Reconstruction” usingex vivogene therapy of autologous tissue offers a new application for immunotherapy in breast cancer with a dual therapeutic effect of both reconstructing the ablative defect and delivering local adjuvant immunotherapy.
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影响因子：
32.4
作者：
DIGHE, AS;RICHARDS, E;SCHREIBER, RD
通讯作者：
SCHREIBER, RD
影响因子：
3.8
作者：
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通讯作者：
Cromwell, D. A.
影响因子：
64.8
作者：
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通讯作者：
Roecken, Martin
影响因子：
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作者：
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通讯作者：
Link W
影响因子：
9.6
作者：
Beecher, S. M.;O'Leary, D. P.;Kerin, M. J.
通讯作者：
Kerin, M. J.