Development of T cell costimulatory ligand-carrying viral vector for anticancer therapy

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03529
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Mie University
• Principal Investigator: Nosaka Tetsuya 三重大学, 医学系研究科, 教授 (30218309)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: T細胞共刺激分子 / ウイルスベクター / 抗腫瘍ウイルス / 細胞傷害性T細胞 / 腫瘍免疫 / OX40 / 4-1BB / GITR

Outline of Final Research Achievements

Cancer therapy entered a new era after development of immune checkpoint inhibitors. However, they cannot always kill cancer cells completely, and researchers are trying to develop agents that synergize to eradicate cancers. We generated a T cell-signaling anti-tumor virus (TAV) by using a novel RNA viral vector BC-PIV which we developed as a gene/protein dual carrier in collaboration with BioComo Inc. TAV was able to induce regression of autologouly transplanted tumor cells after intratumoral injection not only on the injected, but also on the distant site. By screening of the T cell co-stimulatory ligands, we found that BC-PIV/GITRL-OX40L was the most effective TAV among the ligands when introduced into BC-PIV. However, TAV is not a panacea because TAV fuction depends on the timing of the expression of T cell costumulatory receptors. Therefore, we searched helper agents, and co-injection of BC-PIV/cytokine A and BC-PIV/chemokine B was found to synergize with the anti-PD-1 antibody.

Free Research Field

分子生物学、ウイルス学、免疫学、内科学

Academic Significance and Societal Importance of the Research Achievements

がんの克服は人類に残された大きな課題であり、免疫チェックポイント阻害剤（ICI)の開発はがんの治療に大きな革命をもたらしたが、いまだ全てのがんが治るわけではない。現在使用されているICIはがん免疫の「ブレーキ」解除薬である。我々は基礎実験段階であるが、がん免疫の「アクセル」増強薬を開発した。さらに、これらブレーキ解除、アクセル増強に加えてがん細胞を殺すT細胞の疲弊を防ぎ、働き場所に遊走しやすくする補助剤が抗がん作用において大きな効果を持つことを見出した。これらは実用化を目指して社会実装の準備中であるが、実現すれば医学的貢献にとどまらず、医療経済的効果も大きいと考えられる。