Analyses of tumor cell-specific glycan structures for the development of next-generation immunotherapy for pancreatic cancer
| Project/Area Number |
20K17001
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Showa University |
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Principal Investigator |
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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 |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | PIGR / Lectinアレイ / CAR-T / レクチンアレイ / 膵臓がん / レクチン / 免疫療法 / 糖鎖 |
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| Outline of Research at the Start |
固形がんに対するCAR-T療法では、適切な治療標的抗原がまだ同定されていない問題がある。そのため我々は膵臓がんの予後不良因子であり、かつ抗がん剤耐性に関与する分子Olfactomedin-4（OLFM4）を同定した。しかし、OLFM4は一部の正常細胞にも発現を認める。そこで、腫瘍細胞上の糖鎖構造が正常細胞と異なることに着目し、腫瘍細胞に特異的な糖鎖修飾を認識するレクチンの同定を試みる。更にそのレクチンを搭載したCAR-T細胞(Lectin-CAR)を作製して臨床応用へとつなげる基盤的研究を行う。正常細胞と腫瘍細胞とを区別することで腫瘍特異性を向上させた次世代型CAR-T療法の開発を目指す。
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| Outline of Final Research Achievements |
Pancreatic cancer has a poor prognosis and warrants novel predictors of therapeutic efficacy and prognosis. We has demonstrated that Polymeric Immunoglobulin Receptor (PIGR) was involved in resistance against chemotherapies and poor prognosis of pancreatic cancer patients. Therefore, PIGR molecule has been identified as a candidate target antigen for novel CAR-T therapy. We are trying to create specific antibodies against PIGR to be loaded onto CAR-T cells. As soon as the antibodies against PIGR are obtained, we will construct CAR-T cells that bind specifically to PIGR, and load the currently identified “lectin-A” onto the CAR-T cells.
We intended to construct the CAR system that turns “ON” only when both lectin and antibody signals are received. We have already performed the consideration of conditions. The cytotoxic activity and cytokine production capacity of “Lectin-CAR” will be analyzed, and its anti-tumor effect and adverse events will also be investigated in further study.
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| Academic Significance and Societal Importance of the Research Achievements |
CAR-T療法の標的抗原の候補として、抗癌剤耐性に関わる分子や予後不良に関わる分子であるPIGRを同定した。しかしPIGRは一部正常細胞にも発現し、CAR-T療法の標的抗原として正常細胞をも傷害する問題がある。我々はPIGRにおける糖鎖発現を解析し、レクチンAが正常細胞と腫瘍細胞との識別に有用である可能性を示した。特定抗原における糖鎖修飾の違いに着目して、腫瘍細胞上の標的抗原の糖鎖修飾のみを認識するレクチンをCAR-T細胞に搭載するという発想は報告が乏しく、学術的意義は高い。また安全性の高いCAR-T療法の開発に応用できる可能性があり、治療法が少ない膵臓がん患者に対する意義は大きいと考える。
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Report
(4 results)
Research Products
(3 results)
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[Journal Article] High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer.2020
Author(s)
Ohkuma R, Yada E, Ishikawa S, Komura D, Ishizaki H, Tamada K, Kubota Y, Hamada K, Ishida H, Hirasawa Y, Ariizumi H, Satoh E, Shida M, Watanabe M, Onoue R, Ando K, Tsurutani J, Yoshimura K, Yokobori T, Sasada T, Aoki T, Murakami M, Norose T, Ohike N, Takimoto M, Izumizaki M, Kobayashi S, Tsunoda T, Wada S.
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Journal Title
PLoS One
Volume: 10
Issue: 1
Pages: e0226707-e0226707
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Development of a novel cancer diagnostic method targeting glycosylation on specific molecules.2022
Author(s)
渡邊真, 家口勝昭, 大西伸幸, 五嶋翼, 大熊遼太朗, 鈴木梨沙子, 辻まゆみ, 木内祐二, 角田卓也, 内田直樹, 小林真一, 和田聡.
Organizer
第96回日本薬理学会年会/第43回日本臨床薬理学会学術総会
Related Report
