合併放射線治療及免疫療法（電基因法加腫瘤內注射樹突細胞）治療效果之動物實驗初報

Synergistic Anti-Tumor Effect of Combination of Radiotherapy and Immunotherapy by Electro-Gene Therapy plus Intra-Tumor Injection of Dendritic Cell

張志嘉(Chih-Chia Chang) ； 王愈善(Yu-Shan Wang) ； 柯卉玲(Hui-Ling Ko) ； 曾玉華(Yuk-Wah Tsang) ； 季匡華(Kwan-Hwa Chi)

《放射治療與腫瘤學》 15卷1期 (2008/03) Pp. 45-51

https://doi.org/10.6316/TRO/200815(1)45

摘要

目的：有研究指出，腫瘤內注射樹突細胞(dendritic cell)可以引發全身免疫反應，然而腫瘤內的樹突細胞也會因為不容易存活而影響到免疫反應的效果。因此本實驗假設給予第二介白質素(IL-2)及顆粒球巨噬細胞群落刺激因子(GM-CSF)能夠幫助樹突細胞的分化成熟因而增加免疫治療的效果。
材料與方法：我們設計一個能有利於免疫微環境(microenvironment)的方法：在腫瘤處先藉由電衝法(electroporation)將第二介白質素及顆粒球巨噬細胞群落刺激因子的基因帶入腫瘤細胞內，然後再把樹突細胞注入腫瘤內。經由電基因轉殖(EGT)後而壞死的腫瘤細胞會釋出腫瘤抗原給樹突細胞而引發毒殺T細胞(cytotoxic T cells)及活化自然殺手細胞(NK cells)。在本實驗中，我們使用的腫瘤細胞為老鼠腸腺癌細胞(PSA/CT-26細胞)。
結果：我們發現，經過反覆四次的雙基因電基因轉殖(EGT-L-2/GM-CSF)後，再將樹突細胞注射入腫瘤內能明顯抑制腫瘤生長和引發全身性的免疫反應。這種免疫治療的策略能引起大量的T細胞腫瘤內浸潤，更重要的是，免疫治療後的腫瘤顯然由於微環境的改變，將大幅提高腫瘤的放射線敏感度，且經過結合免疫治療與放療的老鼠能引發全身性的免疫反應，防止對側腫瘤接種的成長。
結論：經由本實驗我們發現：合併免疫療法加放射線治療除了能達到更好的腫瘤控制之外也能引發全身性免疫反應而達到預防腫瘤復發的效果。而本研究應該繼續進行免疫機轉的進一步研究。

關鍵字

樹突細胞 ； 電衝法 ； 免疫療法 ； 放射線治療

並列摘要

Purpose: Intra-tumoral (i.t.) injection of dendritic cells (DC) has been demonstrated to be able to evoke the systemic immunological response. Nevertheless, the injected DC are prone to be apoptotic in tumor site. Local secreted IL-2 and GM-CSF help the maturation and functioning of injected DC.
Experimental Design: We developed a method of creating an immunological favorable microenvironment by in situ electroporation of IL-2 and GM-CSF genes followed by injection of DC at tumor site. Necrotic and apoptotic cells from electrical shock may provide antigen source for DC to promote cross-priming of cytotoxic T cells and activate NK cells. PSA/CT-26 cells was used in this study.
Results: 4 repeated cycles of double gene EGT plus i.t. DC significantly inhibited the tumor growth and produced systemic immunity. The combination of double gene EGT and DC treatment induced heavy T cell infiltration inside tumor. Mice successfully treated by the combination of immunotherapy & radiotherapy can induce a systemic immunity to prevent the contralateral tumor challenge. Interestingly, the immunological favorable micro-environment established in the tumor site by this protocol created a highly effective condition for subsequent radiotherapy.
Conclusions: Our findings may have clinical implications in achieving better local control and prevention of systemic relapse through the combination of immunotherapy and radiotherapy. Further study for the mechanism is warranted.

並列關鍵字

Dendritic cells ； Electroporation ； Immunotherapy ； Radiotherapy