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単細胞分析により,CAR-T免疫療法の潜在的腫瘍外標的としてCD19を発現する脳壁細胞が特定される

Kevin R Parker ¹, Denis Migliorini ², Eric Perkey ³

¹Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA.
²Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Translational Research in Onco-Hematology and Department of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
³Graduate Program in Cellular and Molecular Biology and Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA; Division of Hematology-Oncology, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
⁵Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Functional and Molecular Imaging Laboratory, Research Branch, Sidra Medicine, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar.
⁷Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁹Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰Division of Hematology-Oncology, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹²Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹³Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
¹⁴Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

⁰Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA.

Cell +

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2020年9月22日

PubMedで要約を見る

まとめ

B細胞の悪性腫瘍を標的としたCD19指向の免疫療法は神経毒性を引き起こします. 研究者らは,CD19が脳壁細胞に発現することを発見し,この副作用の新たなメカニズムを示唆しました.

科学分野

神経科学
免疫学
腫瘍学

背景

CD19を標的とする免疫療法は,B細胞の悪性腫瘍に対して有効である.
これらの治療は致命的な脳腫を含む重大な神経毒性を引き起こします.
この神経毒性の根本的なメカニズムは完全に理解されていません.

研究の目的

脳細胞のCD19発現を調査する.
CD19 標的治療における神経毒性の潜在的な標的メカニズムを特定する.
血脳障壁の壁細胞の神経毒性への関連性を評価する.

主な方法

人間の脳サンプルから得られた単細胞RNAの配列解析
免疫ヒストケミストリーによる脳壁細胞におけるCD19タンパク質発現の確認
人とマウスの壁画細胞におけるCD19発現の比較

主要な成果

CD19は人間の脳内の壁細胞によって発現します.
この発現は早期発育から成人期まで脳の様々な領域に現れます
ネズミの壁の細胞は,ヒトの細胞と比較してCd19の発現が低い.

結論

壁細胞のCD19発現は,神経毒性の潜在的な標的メカニズムを表しています.
ヒトの単細胞アトラスはより安全な免疫療法の設計に役立つツールです
臨床前モデルでは,異なるCD19発現により,ヒトの神経毒性を完全に再現することができない.

関連する概念動画

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.