Novel gene therapy strategy for ovarian cancer using adeno-associated virus-CRISPR/Cas9

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K18171
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Wakayama Medical University
• Principal Investigator: Yahata Tamaki 和歌山県立医科大学, 医学部, 助教 (90647562)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 卵巣癌 / PD-L1 / AAV-CRISPR/Cas9

Outline of Final Research Achievements

In this study, we developed a novel gene immunotherapy model targeting PD-L1 in ovarian cancer using AAV-CRISPR/cas9 and investigated its efficacy. We produced PD-L1-AAV particles for knockout of PD-L1. In the peritoneal dissemination model, the survival time was significantly longer in the PD-L1-AAV particles-treated group compared to the control group. Immunohistochemically, the numbers of intratumoral CD4+ T cells, and CD8+ T cells were significantly higher, whereas that of regulatory T cells was significantly lower in the PD-L1-AAV particles-treated group compared to the control group. There were no specific severe adverse events in the organs such as lungs, livers, kidneys, and spleens.
AAV-CRISPR/Cas9 may be a potential gene immunotherapy targeting PD-L1 in ovarian cancer.

Free Research Field

腫瘍免疫学

Academic Significance and Societal Importance of the Research Achievements

卵巣癌におけるPD-L1を標的とした抗体療法の研究は複数報告されているが、AAV-CRISPR/Cas9を用いた卵巣癌の標的遺伝子に対する治療モデルの報告はない。本研究ではAAV-CRISPR/Cas9を用いることで，マウスに直接接種し、腫瘍のPD-L1遺伝子を改変することが可能となった。マウス卵巣癌腹膜播種モデルにおいて、PD-L1-AAV粒子を直接投与することで、腫瘍免疫応答を誘導し、重篤な有害事象を引き起こすことなく、腫瘍抑制効果を示すことが実証された。本研究成果はAAV-CRISPR/Cas9を介したPD-L1を標的とした新規免疫遺伝子治療が、臨床試験に向けての基盤研究となると考える。