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| Title: | 開發可一步驟分化、增殖、並武裝T細胞之雙功能抗體以應用於腫瘤專一性治療
Development of the bispecific antibody to one-step differentiate, expand, and arm T cells for selective tumor therapy |
| Authors: | 陳易柔
Chen, Yi-Jou |
| Contributors: | 中草藥臨床藥物研發博士學位學程
莊國祥 |
| Keywords: | 抗腫瘤/抗CD3雙功能抗體;毒殺型T細胞;腫瘤專一性T細胞;腫瘤治療;腫瘤專一性武裝型T細胞
Anti-Tumor/Anti-CD3 bispecific antibody;cytotoxic T cell;tumor specific T cell;cancer treatment;BsAb armed-T cell |
| Date: | 2019-07-24 |
| Issue Date: | 2020-02-25 13:19:16 (UTC+8) |
| Abstract: | T細胞免疫療法為癌症之一種新興治療策略；然而，傳統方法所培育之T細胞缺乏腫瘤專一性，為使其具有腫瘤專一性，則須花費長時間於活體外培育訓練，或利用反轉錄病毒進行基因轉殖，使改造後之T細胞面臨癌化風險。為克服這些問題，我們開發一新型雙功能抗體(BsAb)培育腫瘤專一性T細胞之技術平臺，僅需將anti-Tumor/anti-CD3 BsAb加至人類週邊血液單核球(PBMC)培養基中，即可於十天內將PBMC分化、增殖為CD3+CD8+T細胞，且於培育過程中雙功能抗體即可同時修飾於T細胞表面，一步驟將其轉換為高純度之腫瘤專一性武裝型T細胞(anti-Tumor BsAb armed-T cell，純度>90%)。目前，我們已成功開發多種不同構型如anti-Tumor Fab/anti-CD3scFv、anti-Tumor scFv/anti-CD3Fab、anti-Tumor scFv/anti-CD3scFv、anti-Tumor Hole/anti-CD3 Knob 雙功能抗體，並具備多種anti-Tumor (PSMA、EGFR……)腫瘤辨識端之變化，各種雙功能抗體均已證實可於活體外快速培育出腫瘤專一性T細胞；活體外細胞實驗及帶有人類腫瘤之小鼠試驗，均證實anti-Tumor BsAb armed-T cell可高效率標靶毒殺腫瘤，且不會產生過度細胞激素釋放或顯著毒性。本研究克服傳統方法須使用抗原呈現細胞，或使用反轉錄病毒進行基因轉殖之技術方可培育出腫瘤專一性T細胞之問題；是一套快速培育、非病毒基因轉殖、高純度且成本合宜之腫瘤專一性T細胞建置平台，將提供全球癌症病患一更為安全、有效、且得以負擔之新型T細胞治療策略。
T cell immunotherapy is one of new strategies for cancer treatment. However, generation of tumor-specific T cell therapy is often limited by the need for laborious incubation processes or the need for retrovirus-based gene transfection. Here, we present a non-genetically engineering technology to rapid develop tumor-specific T cells. By using anti-tumor/anti-CD3 BsAb of special structures to culture human peripheral blood mononuclear cells, tumor specific BsAb-armed T cells can be generated, cultured and expanded with purity over 90% in 10 days. Now, we have developed several anti-tumor/anti-CD3 BsAb with different structure, including: anti-Tumor Fab/anti-CD3scFv, anti-Tumor scFv/anti-CD3Fab, anti-Tumor scFv/anti-CD3scFv, anti-Tumor Hole/anti-CD3 Knob BsAb, and all the BsAb have the ability to differentiate and expand the BsAb armed T cells. The BsAb armed T cells can efficiently accumulate at tumor site in vitro and in vivo. The release of cytotoxins (perforin and granzyme) and cytokines (TNF-α and IFN-γ) from BsAb-armed T cells dramatically raise after contacting tumor cells, which can effectively eliminate tumor cells. Importantly, human tumor bearing SCID mice treated with BsAb-armed T cells did not show obvious cytokine release syndrome and tissue toxicity. The BsAb armed T cell technology is a fast-culturing and low-cost platform to generate high pure tumor-specific T cells without genetically engineering. |
| Description: | 博士
指導教授：莊國祥
共同指導教授：鄭靜枝
委員：何元順
委員：林時宜
委員：羅傅倫
委員：鄭添祿
委員：卓爾婕 |
| Data Type: | thesis |
| Appears in Collections: | [中草藥臨床藥物研發博士學位學程] 博碩士論文
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