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<p>Chimeric antigen receptor (CAR) T cells can mediate durable complete responses in individuals with certain hematologic malignancies, but antigen downregulation is a common mechanism of resistance. Although the native T cell receptor can respond to very low levels of antigen, engineered CARs cannot, likely due to inefficient recruitment of downstream proximal signaling molecules. We developed a platform that endows CAR T cells with the ability to kill antigen-low cancer cells consisting of a membrane-tethered version of the cytosolic signaling adaptor molecule SLP-76 (MT-SLP-76). MT-SLP-76 can be expressed alongside any CAR to lower its activation threshold, overcoming antigen-low escape in multiple xenograft models. Mechanistically, MT-SLP-76 amplifies CAR signaling through recruitment of ITK and PLCγ1. MT-SLP-76 was designed based on biologic principles to render CAR T cell therapies less susceptible to antigen downregulation and is poised for clinical development to overcome this common mechanism of resistance.</p>

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Engineering T cells with a membrane-tethered version of SLP-76 overcomes antigen-low resistance to CAR T cell therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月23日

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  • Maria Caterina Rotiroti,
  • Aidan M. Tousley,
  • Hoyin Chu,
  • Marco Herrera-Barrera,
  • Antigoni Manousopoulou,
  • Won-Ju Kim,
  • Yajie Yin,
  • Thomas Spencer Parish,
  • Aniela Mitchell,
  • Malcolm Holterhus,
  • Lea Wenting Rysavy,
  • Guillermo Nicolas Dalton,
  • Katherine Ann Freitas,
  • Gernot Kaber,
  • Korbinian N. Kropp,
  • Christopher A. Klebanoff,
  • Ansuman T. Satpathy,
  • Leo D. Wang,
  • Caleb A. Lareau,
  • Robbie G. Majzner

摘要

Chimeric antigen receptor (CAR) T cells can mediate durable complete responses in individuals with certain hematologic malignancies, but antigen downregulation is a common mechanism of resistance. Although the native T cell receptor can respond to very low levels of antigen, engineered CARs cannot, likely due to inefficient recruitment of downstream proximal signaling molecules. We developed a platform that endows CAR T cells with the ability to kill antigen-low cancer cells consisting of a membrane-tethered version of the cytosolic signaling adaptor molecule SLP-76 (MT-SLP-76). MT-SLP-76 can be expressed alongside any CAR to lower its activation threshold, overcoming antigen-low escape in multiple xenograft models. Mechanistically, MT-SLP-76 amplifies CAR signaling through recruitment of ITK and PLCγ1. MT-SLP-76 was designed based on biologic principles to render CAR T cell therapies less susceptible to antigen downregulation and is poised for clinical development to overcome this common mechanism of resistance.