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Background <p>Chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating malignant diseases, yet its efficacy is often limited by challenges such as controllability and the lack of tumor-specific antigens. Adapter CAR (AdCAR) T cells address these limitations by redirecting T cell activity through adapter molecules rather than direct interaction with tumor-associated antigens, offering an on-/off- switch mechanism and the potential for multitargeting. While functionality of AdCAR T cells has been demonstrated in various models, the underlying AdCAR T cell response to differing adapter concentration and its comparison to conventional CAR T cells remain poorly characterized.</p> Methods <p>In this study, we systematically examined adapter-dependent AdCAR T cell responses using functional assays and single-cell RNA sequencing in an acute myeloid leukemia model.</p> Results <p>Adapter concentration was found to determine AdCAR T cell activation dynamics, transcriptional states and metabolic reprogramming. At low adapter concentrations, an interferon-responsive state was observed, while high concentrations induced strong cytolytic activity, cytokine secretion, and metabolic shifts toward glycolysis and oxidative phosphorylation. Importantly, increasing adapter concentrations enhanced tumor control of sub-optimally activated AdCAR T cells, demonstrating the platform’s tunability. A hallmark gene signature was identified across different adapters and target cells, comprising the interferon-responsive gene <i>MX1</i> and activation-associated genes including <i>ENO1, HSP90AB1</i>, and <i>RRM2</i>.</p> Conclusions <p>Our findings provide a mechanistic framework for tuning AdCAR T cell responses and offer critical insights for optimizing adapter dosing to enhance the safety and efficacy of tunable CAR T cell therapies.</p>

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Transcriptional and functional profiling reveals unique activation of Adapter CAR T cells in acute myeloid leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Nele Knelangen,
  • Ulrika Bader,
  • Evangelia Maniaki,
  • Boris Engels,
  • Luca Gattinoni,
  • Joerg Mittelstaet

摘要

Background

Chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating malignant diseases, yet its efficacy is often limited by challenges such as controllability and the lack of tumor-specific antigens. Adapter CAR (AdCAR) T cells address these limitations by redirecting T cell activity through adapter molecules rather than direct interaction with tumor-associated antigens, offering an on-/off- switch mechanism and the potential for multitargeting. While functionality of AdCAR T cells has been demonstrated in various models, the underlying AdCAR T cell response to differing adapter concentration and its comparison to conventional CAR T cells remain poorly characterized.

Methods

In this study, we systematically examined adapter-dependent AdCAR T cell responses using functional assays and single-cell RNA sequencing in an acute myeloid leukemia model.

Results

Adapter concentration was found to determine AdCAR T cell activation dynamics, transcriptional states and metabolic reprogramming. At low adapter concentrations, an interferon-responsive state was observed, while high concentrations induced strong cytolytic activity, cytokine secretion, and metabolic shifts toward glycolysis and oxidative phosphorylation. Importantly, increasing adapter concentrations enhanced tumor control of sub-optimally activated AdCAR T cells, demonstrating the platform’s tunability. A hallmark gene signature was identified across different adapters and target cells, comprising the interferon-responsive gene MX1 and activation-associated genes including ENO1, HSP90AB1, and RRM2.

Conclusions

Our findings provide a mechanistic framework for tuning AdCAR T cell responses and offer critical insights for optimizing adapter dosing to enhance the safety and efficacy of tunable CAR T cell therapies.