Research toward the development of beta-TCP as a novel vaccine adjuvant.

• Project/Area Number: 18K12094
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 90120:Biomaterials-related
• Research Institution: Shizuoka Cancer Center Research Institute
• Principal Investigator: Maruyama Kouji 静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (20311417)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: β-TCP / オートファジー修飾物質 / Toll様受容体 / がん抗原 / がん免疫療法 / ワクチン アジュバント / オートファジー / インフラマソーム

Outline of Final Research Achievements

Beta-tricalcium phosphate (b-TCP), which is clinically used as a bone substitute material, has an immunostimulatory effect. In mouse tumor models, combination therapy with b-TCP, tumor antigens (TA), and Toll-like receptor ligands (TLRL) induces potent antitumor effects. In this study, we searched for autophagy (AP) modifiers that enhance the immunostimulatory effect of b-TCP using inflammasome activation as an index in vitro, and evaluated the antitumor effect in mouse tumor models. As a result, two AP inhibitors were selected as candidates by in vitro screening, but none of the mouse antitumor studies showed an enhancing effect on b-TCP. On the other hand, these two AP inhibitors were shown to induce potent antitumor effects when used in combination with TA and TLRL. Although these results deviate from the original objectives, but we believe that the findings provide completely novel insights that pave the way for the application of TLRL and AP inhibitors to cancer immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

現在、がん治療の領域では、細胞毒性をもつ化学療法剤による古典的化学療法から、がん細胞特異的な分子標的薬や免疫系を活性化する免疫チェックポイント阻害剤(ICPI)による治療法へと急速な方向転換が始まっています。特にがん免疫療法は、がん患者さんが本来持つ身体の機能をアップさせてがんと戦う治療法であり、有効性が高く副作用が弱い治療法として大変期待されています。ノーベル賞を受賞した本庶佑博士の開発したICPIのオプジーボをはじめ、有効な薬剤の多くが大変高価な抗体医薬です。本研究の成果は、免疫系を活性化するより安価な小分子化合物の開発・臨床応用に道を拓くもので、がん免疫療法の新しい流れに資するものです。