2018-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647301摘要：傳統上，癌症患者的治療模式主要透過以手術治療，放射治療和化學治療的方式。然而這些治療方式除了殺死癌細胞外，也同時會傷害健康的細胞。理想的癌症治療模式應該能夠同時清除全身腫瘤在多個站點中的主體，同時也能特異性的區分腫瘤和非腫瘤細胞。因此具抗原特異性腫瘤免疫治療也成為一種具有吸引力的嶄新腫瘤治療方式。我們在最近的研究發展出利用以細胞(Meso-VAX)為基礎並結合腺相關病毒嵌合介白質-12(AAV-IL-12)的卵巢癌免疫治療策略。研究結果中顯示這種結合具抗原特異性免疫治療與溶瘤病毒合併基因治療的方式能展現出具腫瘤相關性抗原(TAA)的癌症細胞的特異性免疫反應，能有效的控制癌細胞的成長，其治療效果遠較單一進行免疫治療的效果更佳。Cyclophilin B (CypB) 已經被證實能在肝癌、乳癌及卵巢癌高度表達，且被認為是一種具有發展潛力的腫瘤相關性抗原。因此我們以現有發展為基礎，嘗試進行以通用性抗原CypB為標的之免疫治療策略。另一方面以腺相關病毒載體的缺點是能載入的基因大小受到限制，也由於40%-80%的成人中已經有過腺病毒感染可能會引起腺病毒免疫排斥的現象，因此發展嶄新的病毒載體為基礎的免疫治療以強化現有的疫苗，將能有效提升本免疫治療方式對腫瘤抗原的應用性。牛痘病毒載體能有效提升載入基因容載量，且能會引起體液免疫以及細胞免疫反應。因此發展以牛痘病毒為嶄新的病毒載體並提升具抗原特異性免疫反應以強化腫瘤治療效果可能提供了癌症免疫治療的新策略與新方向。此外在癌症微環境中，免疫抑制細胞也能藉由抑制CD4+輔助T 細胞及CD8+細胞毒性T 細胞而抑制宿主免疫功能。因此我們也將進一步探討剔除這些免疫抑制細胞是否可以促進DNA 疫苗合併溶瘤病毒此種免疫治療的策略。因此我們提出了這個三年的計畫將發展嶄新的具抗原特異性免疫治療策略，重點放在去氧核醣核酸疫苗結合溶瘤病毒對提升免疫治療效果的影響。本計畫的目標如下：第一、構築以IGF-1 結合腫瘤相關性抗原CypB (IGF-1/CypB)的DNA 疫苗與牛痘病毒載體免疫治療方式能否提供更好的抗原特異性免疫反應及抑制動物模式中卵巢癌發生。第二、我們將評估IGF-1/CypB 結合牛痘病毒載體免疫治療免疫抑制細胞剔除是否能進一步增強卵巢癌的動物研究模式。第三、我們將建立具CypB 特異性免疫反應的臨床試驗分析平台。在以CypB 相關的癌症研究模式下，本計畫的研究成果將有機會對未來癌症病人的免疫治療，提供新的治療策略與理論基礎。<br> Abstract: Traditionally, the available forms of treatment-surgery, radiation therapy, and chemotherapy are mainly cytoreductive treatment modality for cancer patients. Besides, these treatment modalities in addition to killing cancerous cells, healthy cells are also destroyed. The ideal cancer treatment should be able to eradicate systemic tumors at multiple sites in the body while having the specificity to discriminate between neoplastic and non-neoplastic cells. In this regard, antigen-specific cancer immunotherapy represents an attractive approach for cancer treatment.Our previous investigations have developed new strategies of ovarian cancer immunotherapy by using the cell (Meso-VAX) based vaccines combined with adeno-associated virus encoded interleukin-12 (AAV-IL-12). Our results revealed that the combination of immunotherapy and virotherapy demonstrated a tumor-associated antigen (TAA)-specific immunological cyto-killing effect and effectively control the growth of tumors. It also showed that combinational immunovirotherapy has a more superior tumor therapeutic effect than respective immunotherapy or virotherapy.Cyclophilin B (CypB) has been identified as TAA expressed on several kinds of human cancers including hepatoma (HCC), breast and ovarian cancer. So CypB might be a potential TAA for the development of cancer prevention and therapy for several kinds of human cancers. Therefore, based on our existing development, we could like to investigate the immunotherapeutic strategy could be also used by targeting cancer common antigen CypB. On the other hand, AAVs vaccination might induce potential immunological rejection due to the transgene capacity limitation and about 40-80%pre-existing immunity in humans. . To develop a novel viral-based immunotherapy to increase antigen-specific responses could enhance the immunotherapeutic efficiency. Vaccinia viral vector could increase transgene capacity and induce both humoral and cellular immunity. To develop a vaccinia viral vector to increase antigen-specific immunity and anti-tumor responses might provide a new strategy and direction for cancer immunotherapy. Besides, immune suppressor cells could inhibitboth CD4+ helper and CD8+ cytotoxic T cells to decrease host immunity in tumor micronvironment.We will further evaluate if immune suppressor cells could enhance immunotherapy by DNA vaccine combined with oncolytic virotherapy.So we propose this three-year proposal to develop novel antigen-specific cancerimmunotherapeutic strategies. We will focus on the immunotherapeutic responses by combining DNA vaccine with vaccinia vaccination therapy. The aims of this proposal are as follows: First, we will develop insulin-like growth factor-1 linked with cancer associated antigen- CypB (IGF-1/ CypB)chimeric DNA vaccines combined with vaccinia will generate better immune responses and antiovarian cancer tumor growth in animal model. Second, we will evaluate if the IGF-1/ CypB DNA vaccine combined vaccinia immunotherapy with immune suppressor cells depletion could be further enhance ovarian cancer immunotherapy efficiency in animal models. Third, we will establish theCypB -specific immunological platforms through the clinical samples for future clinical trials. By targeting CypB -related cancer model, our results of this proposal will have the possibility to provide innovative strategies and novel anti-tumor mechanism(s) on the immunotherapy of cancer patients in the future.腫瘤免疫治療