| Project/Area Number |
20H04524
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 90120:Biomaterials-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Cabral Horacio 東京大学, 大学院工学系研究科(工学部), 准教授 (10533911)
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| Co-Investigator(Kenkyū-buntansha) |
垣見 和宏 東京大学, 医学部附属病院, 特任教授 (80273358)
内田 智士 東京大学, 大学院工学系研究科(工学部), 特任助教 (20710726)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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| Keywords | CAR T cells / Nanomedicine / Polymeric micelles / mRNA / Cancer / Antibody fragment / in vivo CAR T / nanomedicine / immunotherapy / cancer |
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| Outline of Research at the Start |
We will first develop a series of T-cell targeted mRNA-loaded nanocarriers. These nanocarriers will be optimized for stability, targeting and protein production in vitro.
Promising formulations will then be tested in vivo. to determine the targeting efficacy to the CD8 T cells, the production of CAR T cell in situ and the antitumor activity against models of leukemia and solid tumors. Finally, we will check the toxicity of the treatments.
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| Outline of Final Research Achievements |
Chimeric antigen receptor (CAR) T cells are programmed with cancer-specific antigen receptors that direct them to kill cancer cells. Here, we aim to generate CAR T cells in situ by targeted delivery of CAR encoding messenger RNA (mRNA) with polymeric micelles. The mRNA-loaded micelles were constructed from novel biocompatible block copolymers and their surface was modified with anti-CD8 antibody fragments (Fab’). The micelles were stable in physiological conditions and protected mRNA from degradation from nucleases. The micelles also promoted targeted delivery to CD8+ T cells and increased mRNA translation. The Fab’-installed micelles were used to induce anti-CD19 CAR on CD8+ T cells, which allowed them to effectively kill cancer cells in vitro. After injecting the Fab’-installed micelles inside tumors, we were able to generate anti-CD19 CAR on the CD8+ T cells in tumors and in sentinel lymph nodes.
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| Academic Significance and Societal Importance of the Research Achievements |
CAR T細胞療法は、臨床で有効ですが、高価で毒性があります。T 細胞を in situ で生成することで、CAR T 細胞の製造に必要な手間のかかる ex vivo プロセスを回避し、必要としている患者さんのための既製の治療法に変えることができるのです。今回の成果は、mRNAを搭載したミセルがCAR T細胞をin situで生成する可能性と、この細胞ががん細胞を効果的に殺傷する能力を示しています。
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