2020 Fiscal Year Final Research Report
Combination cancer immunotherapy with antigen-specific agonistic TLR4 antibody and immune checkpoint inhibitors
| Project/Area Number |
18K06651
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | International University of Health and Welfare (2020)
Tohoku University (2018-2019) |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | Toll様受容体 / がん免疫療法 / 自然免疫 / 免疫チェックポイント / 低分子創薬 / CD73 / アデノシン受容体 / アジュバント |
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| Outline of Final Research Achievements |
Immune-checkpoint blockade is a novel therapy for cancer. However, its therapeutic efficacy is currently limited due to diverse immune suppressive mechanisms. The purpose of the study was to overcome these limitations and promote the development of novel combined cancer immunotherapy. A TLR4-stimulating antibody, not microbial TLR4 agonist lipopolysaccharide, has been shown to enhance a therapeutic effect of a PD-1 inhibitory antibody. Secondly, low-molecular-weight compounds with inhibitory activity for PD-L1 expression and CD73/adenosine receptor A2A-mediated immune suppressive pathway have been discovered by screening small molecule libraries, respectively. These results will facilitate the development of novel antitumor adjuvants to enhance the response rate and therapeutic efficacy of immune-checkpoint blockade therapy. The discovered compounds are expected to contribute to the development of new therapeutic drugs with immune-checkpoint blockade activity for cancer immunotherapy.
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| Free Research Field |
免疫学・生化学・細胞生物学・分子生物学
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| Academic Significance and Societal Importance of the Research Achievements |
免疫チェックポイント阻害療法が成功し、がんは免疫で治せる時代が到来した。しかし、成功例のPD-1阻害抗体でさえ、その奏効率は高くて3割である。がん免疫病態は冗長で複雑、かつ多様なため、PD-1/PD-L1経路「非」依存的免疫抑制経路を標的とした新規治療戦略・治療薬が切望されている。本研究では、PD-1阻害抗体の治療効果を向上させるTLR4刺激抗体アジュバントの複合がん免疫療法、PD-1免疫抑制経路を遮断しうる低分子化合物、そして、PD-1「非」依存的経路を遮断しうるCD73阻害化合物を発見することに成功した。これら研究成果には、現行のがん治療を発展させる社会的かつ学術的な意義がある。
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