我們一直很關注PD-1&CTLA-4的資訊，協助的患者裡頭，也有同時併用PD-1和細胞療法。當然也有些就僅使用PD-1藥品，定期的訪談時發現，其中有幾位出現PD-1抗藥性，雖然不是我們的客戶，但還是忍不住在想，是否有什麼相關研究資訊，可以提供給他們，增加藥品的有效率。
這陣子找到兩篇干擾素和免疫藥品出現抗藥性的相關研究，文章標題為 Tumor Intern Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade，這是一個很令人振奮的資訊，摘要的部分裡面有提到，該臨床顯示干擾素對於調節免疫分子藥的抗藥性有關聯*1。干擾素在這裡頭的影響機制請參考此一圖示。
另外2016年9月1號，文章為Loss of INF-γ Pathway Genes in Tumor Cell as a Mechanism of Resistance to Anti-CTLA-4 Therapy，發表在NCBI，關於干擾素伽瑪（interferon gamma, IFN-γ）的基因突變是被黑色素瘤用來抵抗Ipilimumab(Yervoy)的關鍵。*2
從這兩篇文章看來，這個IFN-γ看似相當重要。醫療助手在協助患者接受日本各地的治療當中，其中在東京帝國飯店的RISO診所除了提供融合細胞療法外，還有其中有施打介白素中的IL-12，介白素（interleukin）是一組細胞因子（分泌的信號因子）。最早發現在白血球中表達做為細胞間信號傳達的手段。實際上白血球介白素可以由多種細胞產生。免疫系統功能，在很大程度上依賴於介白素。介白素又分為許多IL-1~33，這些資料是參考wiki百科裡頭。其中的IL-12這是一種主要來源是巨噬細胞，這種激素可刺激自然殺手細胞，促使輔助型T細胞1（TH1 Cells）的作用增強，促使Th0走向Th1，可能可以抑制食物的過敏反應。以及增加干擾素伽瑪（interferon gamma, IFN-γ）的分泌*3 或許這也是該醫療機關持續不斷使用此一療法原因之一吧！
備註：
*1 “Tumor Intern Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade”, abstract: Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.
*2 ”Loss of INF-γ Pathway Genes in Tumor Cell as a Mechanism of Resistance to Anti-CTLA-4 Therapy”, abstract: Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.
