2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/646433摘要：鼻咽癌是好發於國人相當特殊的癌症，幾乎絕大多數的鼻咽癌都和EB病毒的感染有關，因此腫瘤細胞所表現的病毒抗原不僅可以作為鼻咽癌的診斷工具，還能作為治療上的重要標靶。目前鼻咽癌的治療主要是以化學治療及放射治療為主，在腫瘤的範圍不大之早期病人，化學治療及放射治療的效果相當不錯，可是若腫瘤的範圍廣泛或已經發生轉移時往往治療的效果就無法令人滿意了。近年來的研究發現免疫治療具有成為鼻咽癌正式治療模式的潛力，先期的人體臨床試驗結果顯示免疫治療能夠大大地增強鼻咽癌病人針對EB病毒的特異性免疫反應，這些結果更大幅提升發展針對EB病毒抗原作為鼻咽癌免疫治療的合理性。鼻咽癌的免疫治療可以用在高危險群病人(例如第四期病人)完成化學治療及放射治療後的輔助治療，也可單獨或合併化學治療用在治療已經發生遠端轉移的病人。免疫治療的品項及方法很多，而本研究主要的內容是著重在發展兩種癌症疫苗(樹突細胞疫苗及DNA疫苗)以作為鼻咽癌的免疫治療。樹突細胞疫苗在早期的臨床試驗中已經得到相當令人鼓舞的初步成果，DNA疫苗相較於其他疫苗則具有許多的優勢，它不僅可以用來預防病毒感染引起的癌症，更重要的是它還可以用來作為癌症的治療。在本研究的第一年中我們將要建立一個免疫健全的小鼠動物腫瘤模式，腫瘤細胞會穩定表現EB病毒的特定抗原(LMP-1，LMP-2，EBNA-1)，這些抗原將被當作治療的標靶。我們還會將小鼠的樹突細胞培養在不同的高分子生物薄膜上，篩選出最適合樹突細胞生存及活化的生醫材料。除此之外，我們還會合成各種不同的DNA疫苗，去選出效果最好的DNA疫苗。在本研究的第二年中我們將會合成不同的樹突細胞疫苗，然後篩選效果最好的樹突細胞疫苗。我們還會選取不同之FDA核准的高分子生醫材料作為DNA疫苗之輔劑，並篩選出效果最好之生醫材料。在本研究的第三年中我們將會調整樹突細胞疫苗及DNA疫苗之各種治療參數，以求找出最好的治療參數。同時還會完成利用樹突細胞疫苗及DNA疫苗治療腫瘤肺臟轉移之動物實驗。我們相信本研究的結果不僅具有相當大的學術價值，且在未來臨床上發展鼻咽癌之免疫治療上將具有極大的轉譯潛力。<br> Abstract: Nasopharyngeal carcinoma (NPC) is rare in most populations around the world but common in Southeast Asia including Taiwan. Almost all non-keratinizing and undifferentiated NPCs are associated with Epstein-Barr virus (EBV). The viral antigens expressed by the tumor provide potential targets not only for the diagnosis but also for the treatment of NPC. Currently, the mainstay for the treatment of NPC is radiation and chemotherapy. Indeed, this is frequently successful when the extent of the tumor is small and confined. However, when disease is advanced at diagnosis and where metastatic spread has become apparent, the treatment results are often dismal. Recent studies have provided some encouragement that immunotherapeutic intervention may be a realistic treatment option for NPC. Preliminary clinical trials show that it is feasible to boost EBV-specific immune responses in NPC patients and provide further rationale to explore EBV as a target for the immunotherapy of NPC. Immunotherapy can be used as an adjuvant treatment to high risk patients who have finished chemoradiation. Or it can be used alone or in combination with chemotherapeutic agents for patients who have developed distant metastases. In this study, we will mainly focus on the development of two types of vaccines, DC-based vaccine and DNA vaccine, for the immunotherapy of NPC. DC-based vaccines have gained inspiring results from early clinical trials. DNA vaccination possesses many potential advantages over other vaccine strategies. It may be used as a both prophylactic and therapeutic vaccine. In the first year of this study, we will establish an immuno-competent mouse tumor model. The tumor cells will be positive for EBV EBNA-1, LMP-1, or LMP-2, and these EBV associated genes will be served as targets for our tumor vaccines. We will also find the polymeric biomembrane that will best improve the survival and maturation of DC. Different constructs of DNA vaccines will be tried and the best vaccine will be identified. In the second year, different DC-based vaccines will be constructed and the best vaccine will be identified. Different FDA-approved polymers will be screened and the most potent delivery vehicles of DNA vaccination will be identified. In the third year, treatment parameters of DC-based vaccines and DNA vaccines will be adjusted and the best treatment parameter will be identified. We will also complete the experiments of treatment of lung metastasis with tumor vaccines (both DC-based vaccines and DNA vaccines). We believe this study not only possesses great academic impact, but also possesses great translational potential to the further development of immunotherapy for NPC in the clinical setting.鼻咽癌EB病毒免疫治療樹突細胞DNA疫苗nasopharyngeal carcinomaEpstein-Barr virusimmunotherapydendritic cellDNA vaccine