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Background <p>Genetic alteration of the MET receptor tyrosine kinase frequently occurs in glioblastoma (GBM). Clinically, bevacizumab treatment results in MET signaling activation, leading to GBM recurrence with a more malignant phenotype. While MET has been a promising therapeutic target, MET inhibitors have not been successful in treating GBM patients. MET-directed chimeric antigen receptor (CAR) T cells hold the promise of targeting MET-positive GBM regardless of genetic alterations or kinase activity.</p> Methods <p>GBM patient-derived xenografts (PDX) harboring <i>MET amplification</i> (<i>MET</i><sup><i>amp</i></sup>) or <i>PTPRZ-MET fusion</i> (<i>ZM</i>) were propagated in vivo followed by glioma stem cell (GSC) isolation. Cell-based assays were used for comparing GSC survival in response to MET inhibitors and CAR T cells. Multi-panel cytokine release was analyzed to profile MET-CAR T cell activation during co-culture with GBM. Orthotopic tumor growth and real-time imaging were performed to evaluate MET-CAR T cell therapeutic efficacy in vivo.</p> Results <p>Although GBM are heterogeneous tumors, neuro-sphere cells isolated from <i>MET</i><sup><i>amp</i></sup> or <i>ZM fusion</i> PDX tumors showed universal cognate genetic MET alteration along with GSC markers such as SOX2 and nestin. Both <i>MET</i><sup><i>amp</i></sup> and <i>ZM fusion</i> tumors showed MET overexpression but only the <i>MET</i><sup><i>amp</i></sup> cells presented activated MET signaling which was vulnerable to MET inhibitors. In contrast, MET-CAR T cells specifically inhibited all MET-positive tumor growth regardless of MET activation status<i>.</i></p> Conclusions <p>Whereas MET inhibitors are effective in MET-active tumors, MET-CAR T cells eradicate MET-positive GBM growth in an antigen-dependent manner, demonstrating a promising therapeutic approach for treating MET-positive GBM. MET overexpression, especially <i>MET</i><sup><i>amp</i></sup> and <i>ZM fusion</i> may be used to predefine the GBM patients for treating with MET-CAR T cell therapy.</p>

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Efficacy of MET-targeting CAR T cells against glioblastoma patient-derived xenograft models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月21日

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  • Anna Qin,
  • Anna Musket,
  • Benjamin Hilton,
  • Johanna Preiszner,
  • Giedre Krenciute,
  • Michael E. Berens,
  • Mingyao Ying,
  • Phillip R. Musich,
  • Qian Xie

摘要

Background

Genetic alteration of the MET receptor tyrosine kinase frequently occurs in glioblastoma (GBM). Clinically, bevacizumab treatment results in MET signaling activation, leading to GBM recurrence with a more malignant phenotype. While MET has been a promising therapeutic target, MET inhibitors have not been successful in treating GBM patients. MET-directed chimeric antigen receptor (CAR) T cells hold the promise of targeting MET-positive GBM regardless of genetic alterations or kinase activity.

Methods

GBM patient-derived xenografts (PDX) harboring MET amplification (METamp) or PTPRZ-MET fusion (ZM) were propagated in vivo followed by glioma stem cell (GSC) isolation. Cell-based assays were used for comparing GSC survival in response to MET inhibitors and CAR T cells. Multi-panel cytokine release was analyzed to profile MET-CAR T cell activation during co-culture with GBM. Orthotopic tumor growth and real-time imaging were performed to evaluate MET-CAR T cell therapeutic efficacy in vivo.

Results

Although GBM are heterogeneous tumors, neuro-sphere cells isolated from METamp or ZM fusion PDX tumors showed universal cognate genetic MET alteration along with GSC markers such as SOX2 and nestin. Both METamp and ZM fusion tumors showed MET overexpression but only the METamp cells presented activated MET signaling which was vulnerable to MET inhibitors. In contrast, MET-CAR T cells specifically inhibited all MET-positive tumor growth regardless of MET activation status.

Conclusions

Whereas MET inhibitors are effective in MET-active tumors, MET-CAR T cells eradicate MET-positive GBM growth in an antigen-dependent manner, demonstrating a promising therapeutic approach for treating MET-positive GBM. MET overexpression, especially METamp and ZM fusion may be used to predefine the GBM patients for treating with MET-CAR T cell therapy.