断続的なPI3Kδ抑制は,抗腫瘍免疫を維持し,irAEsを抑制する

Simon Eschweiler¹, Ciro Ramírez-Suástegui¹, Yingcong Li^1,2

¹La Jolla Institute for Immunology, La Jolla, CA, USA.

Nature

|May 4, 2022

まとめ

調節性T細胞を減少させ,抗腫瘍免疫力を高めることで,頭頸がんにおいて有望であることが示されています. しかし,毒性は現在の投与量を制限し,代替療法の必要性を示唆しています.

科学分野:

免疫学
腫瘍学
薬理学について

背景:

リンパ球機能において重要な役割を果たし,B細胞悪性腫瘍に対する承認された阻害剤である.
PI3Kδ阻害剤 (PI3Kδi) は,臨床前モデルにおいて,固体腫瘍における抗腫瘍免疫を誘発する可能性を示した.
ヒトの固体腫瘍に対するPI3Kδiの有効性および効果は,大部分が特徴づけられていない.

研究の目的:

ヒトの頭頸部がんに対するPI3Kδ阻害剤AMG319の影響を評価する.
PI3Kδ抑制が抗腫瘍免疫および免疫関連有害事象 (irAEs) に与える影響を評価する.
臨床前モデルのPI3Kδi誘発毒性の基礎となるメカニズムを探求する.

主な方法:

AMG319のネオアジュバント,ダブルブラインド,プラセボ対照のランダム化第2相試験は,頭頸部がん患者で実施された.
調節性T細胞と細胞毒性T細胞を含む腫瘍浸透性リンパ球の分析
PI3Kδi誘発の免疫変化と毒性を調査するためにマウスモデルでの単細胞RNA配列化.

主要な成果:

PI3Kδの抑制は,腫瘍に浸透するTレグ細胞を減少させ,ヒトの細胞毒性T細胞の可能性を高めました.
免疫関連の有害事象 (irAEs) の高頻度は,患者の有意な部分で治療中止につながった.
マウスモデルでは,PI3Kδiは全身Treg減少,大腸炎,病原性Tヘルパー17 (TH17) とCD8+T (TC17) 細胞の拡張を引き起こした.

結論:

PI3Kδ抑制は,ヒトの頭頸部がんにおいて免疫調節効果を示すが,試験用量では有意な毒性に関連している.
この毒性は,Tレグ細胞に対する全身的作用と,病原性T細胞サブセットの拡張に関連しているようです.
臨床前モデルの改変された断続的な投与法は,毒性を軽減し,抗腫瘍効果を改善する潜在的な戦略を示唆しています.

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