難治性脳腫瘍の治療法を遺伝子工学的に開発(Genetically engineering a treatment for incurable brain tumors)

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2024-04-22 パデュー大学

パデュー大学の研究チームが、治療法がないとされる神経膠芽腫のための新しい免疫療法を開発中です。この治療法は、従来の自家細胞性療法とは異なり、誘導多能性幹細胞から生成した全く新しい遺伝子改変アロジェニック(他家)免疫細胞を使用します。これにより、患者の血液から細胞を取る必要がなく、無限の細胞供給が可能になります。このアプローチは、マウスを使用した前臨床試験で腫瘍の成長を完全に抑制する効果が確認されており、臨床試験に進む次のステップを計画しています。この研究は「Nature Communications」誌に掲載されています。

<関連情報>

synNotchでプログラムされたiPSC由来のNK細胞は、膠芽腫治療のためにTIGITとCD73の活性を奪う synNotch-programmed iPSC-derived NK cells usurp TIGIT and CD73 activities for glioblastoma therapy

Kyle B. Lupo,Xue Yao,Shambhavi Borde,Jiao Wang,Sandra Torregrosa-Allen,Bennett D. Elzey,Sagar Utturkar,Nadia A. Lanman,MacKenzie McIntosh & Sandro Matosevic
Nature Communications  Published:01 March 2024
DOI:https://doi.org/10.1038/s41467-024-46343-3

難治性脳腫瘍の治療法を遺伝子工学的に開発(Genetically engineering a treatment for incurable brain tumors)

Abstract

Severe heterogeneity within glioblastoma has spurred the notion that disrupting the interplay between multiple elements on immunosuppression is at the core of meaningful anti-tumor responses. T cell immunoreceptor with Ig and ITIM domains (TIGIT) and its glioblastoma-associated antigen, CD155, form a highly immunosuppressive axis in glioblastoma and other solid tumors, yet targeting of TIGIT, a functionally heterogeneous receptor on tumor-infiltrating immune cells, has largely been ineffective as monotherapy, suggesting that disruption of its inhibitory network might be necessary for measurable responses. It is within this context that we show that the usurpation of the TIGIT - CD155 axis via engineered synNotch-mediated activation of induced pluripotent stem cell-derived natural killer (NK) cells promotes transcription factor-mediated activation of a downstream signaling cascade that results in the controlled, localized blockade of CD73 to disrupt purinergic activity otherwise resulting in the production and accumulation of immunosuppressive extracellular adenosine. Such “decoy” receptor engages CD155 binding to TIGIT, but tilts inhibitory TIGIT/CD155 interactions toward activation via downstream synNotch signaling. Usurping activities of TIGIT and CD73 promotes the function of adoptively transferred NK cells into intracranial patient-derived models of glioblastoma and enhances their natural cytolytic functions against this tumor to result in complete tumor eradication. In addition, targeting both receptors, in turn, reprograms the glioblastoma microenvironment via the recruitment of T cells and the downregulation of M2 macrophages. This study demonstrates that TIGIT/CD155 and CD73 are targetable receptor partners in glioblastoma. Our data show that synNotch-engineered pluripotent stem cell-derived NK cells are not only effective mediators of anti-glioblastoma responses within the setting of CD73 and TIGIT/CD155 co-targeting, but represent a powerful allogeneic treatment option for this tumor.

医療・健康
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