摘要:針對癌細胞本身或是其腫瘤血管新生相關的訊息傳導路徑所設計的標靶治療藥物,是目前晚期肝細胞癌的標準治療。然而,目前標靶治療藥物對於延長肝癌病患存活時間的效果,一般而言還是相當有限,且很快會產生抗藥性。肝癌細胞會引發病患的免疫功能抑制。此外,許多標靶治療藥物也有免疫調控的作用。以sorafenib﹝是目前唯一被核准使用於肝細胞癌的標靶治療藥物﹞為例:sorafenib會經由抑制T細胞活化、NK細胞活性、以及樹突細胞﹝dendritic cells﹞成熟等機轉產生免疫抑制效果,這些免疫抑制效果可能減低sorafenib的抗癌療效。我們因此假設,合併免疫治療與標靶治療以扭轉病患的免疫抑制問題,可以進一步改善肝細胞癌藥物治療的療效。針對T細胞活化與增生的調控機轉中重要的控制蛋白所設計的「標靶免疫治療」,是新發展的免疫治療模式。目前研究最多的控制蛋白是CTLA-4及PD-1,兩者均會抑制T細胞之活化。臨床前試驗顯示anti-CTLA-4及anti-PD-1 抗體對於多種癌症均有療效。Anti-CTLA-4抗體已經證實可以延長晚期黑色素細胞癌﹝melanoma﹞的存活時間,而早期臨床試驗顯示anti-PD-1 抗體在多種固態腫瘤及血液腫瘤均有療效。此外,免疫調控劑lenalidomide﹝可以增進T細胞活化以及NK / NK-T細胞之細胞毒殺能力﹞已被核准治療多發性骨髓瘤及骨髓化生不良症候群。這些證據顯示「標靶免疫治療」具有極高的潛力成為新一代的癌症藥物治療。本研究計畫的目標是利用「標靶免疫治療」方式來改善肝細胞癌藥物治療的療效。本計畫的具體目標1.利用免疫功能健全的「正位」﹝orthotopic﹞小鼠肝癌模式,探討標靶免疫治療﹝包括anti-CTLA-4 及anti-PD1 抗體及lenalidomide﹞單獨使用與合併其他標靶治療藥物的療效。藉此以找出最佳的合併治療處方並且澄清可能造成療效協同增強的作用機轉。包括:2. 尋找與肝癌藥物治療療效有關的免疫作用細胞,並探尋可做療效預測指標的免疫相關生物指標。.3. 確立功能性顯影檢查作為肝細胞癌「標靶免疫治療」療效預測指標的角色。將以動態顯影核磁共振攝影﹝dynamic contrast-enhanced magnetic resonance imaging﹞在「正位」小鼠肝癌實驗模式中監測藥物療效,並探討與療效相關之影像學測量指標。本計畫的長期目標是建立一個的「標靶免疫治療」轉譯研究平台,探討肝細胞癌標靶免疫治療的新治療標的以及療效預測指標,以促進未來肝細胞癌相關臨床試驗之進行。
Abstract: Molecular targeted therapy (MTT), which targets signal transduction pathways in cancer cells or tumor vasculature, is the current standard therapy for patients with advanced hepatocellular carcinoma (HCC). However, the survival benefit of MTT is in general modest and drug resistance develops rapidly. HCC tumors may induce immune suppression of the host. In addition, many MTT were found to have immune modulatory effects. For example, sorafenib, currently the only approved MTT for HCC, may have immunosuppressive effects by inhibiting T cell activation, NK cell activity, and dendritic cell maturation. These immunosuppressive effects may compromise the anti-tumor efficacy of sorafenib.We thus hypothesize that, by reversing the immune suppression of the host, combination of MTT with immunotherapy may enhance the therapeutic efficacy in HCC.Molecular targeted immunotherapy, which targets specific checkpoint proteins that play critical roles in regulating T cell activation and proliferation, emerges as a new modality of immunotherapy. The two best characterized checkpoint proteins are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1), both serve as negative regulators of T cell activation. Pre-clinical models showed promising anti-tumor activity of anti-CTLA-4 or anti-PD-1 antibodies in many tumor types. Anti-CTLA-4 antibody has demonstrated overall survival benefit of the in patients with advanced melanoma. Anti-PD-1 antibody has shown promising anti-tumor activity in solid cancers and hematological malignancies. In addition, the immune modulatory agent lenalidomide, which can enhance T cell activation and the cytotoxic effects of natural killer (NK) cells and NK-T cells, has been approved for multiple myeloma and myelodysplastic syndrome. The above evidence indicates that molecular targeted immunotherapy has great potential as the next generation of cancer therapy.The present project aims to improve the efficacy of systemic therapy in HCC by molecular targeted immunotherapy. The specific aims1. To evaluate the anti-tumor efficacy of specific immune modulators (including anti-CTLA-4 and anti-PD1 antibodies and lenalidomide), alone or in combination with MTT using orthotopic, immunocompetent mouse models of HCC. The best combination regimens will be identified and the mechanisms of potential anti-tumor synergy will be clarified. of the present project are:2. To identify immune effector cells that may be associated with treatment efficacy in HCC. Predictive immune-related biomarkers will be explored.3. To verify the usefulness of functional imaging as a predictive biomarker for molecular targeted immunotherapy in HCC. Dynamic contrast-enhanced magnetic resonance imaging will be used in orthotopic HCC models to monitor treatment response. Imaging parameters associated with treatment efficacy will be explored.The long-term objectiveis to establish a translational research platform to explore predictive biomarkers and novel targets for molecular targeted immunotherapy in HCC to facilitate future clinical trials in HCC.