The Development and Improvement of Antigen-Specific Immunotherapy on Cervical Cancer: Focusing on the Influences of Immune Suppressor Cells

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Project title/計畫英文名

Project Number/計畫編號

NSC98-2628-B002-083-MY3

Translated Name/計畫中文名

子宮頸癌抗原特異免疫治療的發展和改良：著重於免疫抑制細胞的影響

Project Principal Investigator/計畫主持人

WEN-FANG CHENG

Funding Organization

Ministry of Science and Technology

Co-Investigator(s)/共同執行人

陳祈安, 孫維仁

Website

link

Start date/計畫起

01-08-2011

Expected Completion/計畫迄

12-07-2012

摘要：近二十年來，癌症已成為台灣十大死因之首。子宮頸癌是台灣女性最常好發和死亡率排名第五位的惡性腫瘤。每年全世界有大約二十萬的婦女死於子宮頸癌。子宮頸癌不但治療費用高，也需要昂貴的篩檢計畫達到早期診斷，更需要經由高額的陰道鏡作為次級篩檢。目前可利用的治療方法諸如手術或放射線治療都會在殺害癌細胞的同時，也會破壞健康的細胞。理想的癌症治療需能消滅全身多處的癌細胞，並要能有特異性的區別是否為正常或腫瘤細胞。我們在先前的研究計畫中最近的研究已經發展出利用低劑量節拍式的(metronomic)化學治療結合免疫治療的嶄新腫瘤治療方式。研究結果中顯示這種結合化學治療與免疫治療的方式展現出對癌症細胞的特異性，更有效的控制癌細胞的成長。這種化學治療結合免疫治療的治療方式其治療效果遠較單一進行化學治療或免疫治療的效果更佳。這種低劑量節拍式的化學-免疫治療方式很可能是經由影響免疫抑制細胞達到較好的效果。目前癌症病人的治療較為困難的是晚期癌症病人的治療。這群病人也常因免疫功能不佳而影響了免疫治療的效果。因此結合化學治療與免疫的治療觀念，可能提供了癌症免疫治療的新策略與新方向。因此我們提出了這個三年的計畫將重點放在免疫抑制細胞的研究並嘗試如何經由抑制免疫抑制細胞進而提升免疫治療的效果。本計畫的目標如下：第一、了解已有腫瘤的宿主施不施打DNA疫苗其免疫系統的改變以及具抗原特異性的DNA疫苗的免疫治療除了提升免疫促進細胞(immuno-effector cells) 之外，是否也會增加免疫抑制細胞(immuno-suppressor cells)？第二、選擇結合不同化療藥物在以不同劑量及療程下，低劑量節拍式的化學-免疫治療是否會影響宿主自身的免疫系統(immune profiles)，包括免疫促進細胞及免疫抑制細胞？第三，結合免疫抑制細胞剔除(depletion)或低劑量節拍式的化學治療在合併免疫治療下能否提升腫瘤的治療效果？在以HPV 相關的子宮頸癌模式下，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。
Abstract: Cancer has become the first cuase of mortality in Taiwan in recent 20 years. Cervicalcancer is the most frequent neoplasm and the fifth mortality rate of malignancies of the womenin the world. It affects half a million women each year and results in about 200,000 womendying of cervical cancer each year worldwide. The conventionally available forms of treatmentfor cervical cancer- surgery, and radiation therapy are cytoreductive treatment modalities, so inaddition to killing cancerous cells, healthy cells are also destroyed in the process. The idealcancer treatment should be able to eradicate systemic tumors at multiple sites in the bodywhile having the specificity to discriminate between neoplastic and nonneoplastic cells.Our previous project has developed a new strategy of cancer therapy by using theconcept of metronomic (low-dose) chemotherapy combined with immunotherapy. Our resultsrevealed that the combination of chemotherapy and immunotherapy demonstrate anantigen-specific immunological cyto-killing effect and effectively control the growth oftumors. It also showed that combinational chemo-immunotherapy has a more superior tumortherapeutic effect than respective chemotherapy or immunotherapy. The combinationalchemo-immunotherapy might be through the mechanism of inhibiting immune suppressorcells to generate better anti-tumor effect. However, the difficulty of treating cancer patients isalways on the treatment of patients with advanced stages. And these patients are always poorresponders to immunotherapy due to their immunocompromise. So the concept ofchemo-immunotherapy can provide a new strategy and direction for cancer immunotherapy.So we propose this three-year proposal to focus on the research of immune suppressorcells and try to promote the effects of cancer immunotherapy via inhibiting the immunesuppressor cells. The aims of this proposal are as follows. First, we would like to investigatethe changes of immune profiles in tumor-bearing hosts with or without DNA vaccine and toelucidate if antigen-specific DNA vaccine-based immunotherapy can not only enhance theantigen-specific immune effector cells, but enhance the immuno-suppressor cells aftervaccination. Second, we would like to understand the influences of combination of variouscytotoxic drugs with immunotherapy in the immuno-profiles of host, including immuneeffector cells and suppressor cells. Third, we would like to elucidate if the combination ofantibody depletion therapy to immuno-suppressor cells or metronomic chemotherapty withimmunotherapy can enhance the cancer therapeutic effects. By targeting HPV-relatedcervical cancer model, our results of this proposal will have the possibility to provideinnovative strategies and novel anti-tumor mechnisms on the immunotherapy of cancerpatients in the future.

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The Development and Improvement of Antigen-Specific Immunotherapy on Cervical Cancer: Focusing on the Influences of Immune Suppressor Cells

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