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エンジニアリングされたCD47は,抗腫瘍免疫を高めるためにT細胞を保護します.

Sean A Yamada-Hunter ^1,2, Johanna Theruvath ¹, Brianna J McIntosh ³

¹Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
²Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
³Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
⁴Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
⁵Masters in Translational Research and Applied Medicine Program, Stanford University School of Medicine, Stanford, CA, USA.
⁶British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
⁷Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
⁸Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
¹⁰Department of Bioengineering, Stanford University, Stanford, CA, USA.
¹¹Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA.
¹²Program in Biophysics, Stanford University, Stanford, CA, USA.
¹³Medical Scientist Training Program, Stanford University, Stanford, CA, USA.
¹⁴Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵Neurosciences Program, Stanford University, Stanford, CA, USA.
¹⁶Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁷Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
¹⁸Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
²⁰Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²¹Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
²²Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²³Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. cmackall@stanford.edu.
²⁴Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁵Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁶Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁷Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁸Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁹Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.

⁰Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.

Nature +

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2024年5月15日

PubMedで要約を見る

まとめ

抗CD47抗体をT細胞療法と併用すると,がん細胞は除去できるが,T細胞も除去できる. CD47変異体によるT細胞設計は,このクリアランスを阻害し,抗腫瘍効果を高めます.

科学分野

免疫学
腫瘍学
バイオテクノロジー

背景

採用されたT細胞とCD47-SIRPα軸阻害剤は,がんに対する有望な免疫療法薬です.
これらのアプローチを組み合わせることで,抗腫瘍効果を高めるが,T細胞のクリアランスに問題がある.

研究の目的

抗CD47抗体と組み合わせた人工T細胞の急速なマクロファージ媒介クリアランスの課題を調査する.
このクリアランスを克服し,T細胞とマクロファージベースのがん治療の有効性を高めるための戦略を開発する.

主な方法

採用されたT細胞 (CAR TまたはTCR T) を用いた抗体投与
CD47抗体媒介クリアランスに抵抗するCD47変種 (47E) を発現させるためのT細胞を設計した.
評価されたT細胞の持続性,マクロファージの募集,および抗腫瘍有効性 in vivo.

主要な成果

抗CD47抗体は,標準のCAR T細胞の迅速なクリアリングを引き起こし,安全スイッチとして作用した.
CD47変異体 (47E) を発現するT細胞は,抗CD47抗体治療後にマクロファージクリアランスに抵抗した.
47E発現するT細胞との併用療法により,マクロファージの募集が強化され,抗腫瘍効果が示されました.

結論

マクロファージは,結合免疫療法におけるT細胞の持続性の主要な調節体である.
エンジニアリングされたCD47変種は,抗-CD47抗体媒介によるT細胞枯渇を克服することができます.
このアプローチは,固体腫瘍の治療を強化するために,T細胞とマクロファージの抗腫瘍活性を同時に活用する戦略を提供します.

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