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Background <p>High-risk ALK-mutant neuroblastoma (NB) presents challenges due to drug resistance and an immunosuppressive tumour microenvironment (TME). Combining molecular targeted therapy with adoptive cell therapy offers a potential therapeutic strategy.</p> Objective <p>To investigate the effects of alectinib, an ALK inhibitor, with disialoganglioside 2 (GD2) chimeric antigen receptor T (CAR-T) cell therapy in overcoming immune evasion in ALK-mutant NB.</p> Methods <p>Interferon gamma-induced programmed death-ligand 1 (PD-L1) expression and ALK signalling were analysed in ALK-mutant NB cells. The combination of alectinib and GD2 CAR-T cells was assessed in vitro, including sequential co-culture assays, and in vivo in an ALK-mutant xenograft model with multiple treatment arms.</p> Results <p>Alectinib suppressed PD-L1 expression by inhibiting ALK downstream pathways, including STAT3 and ERK1/2 phosphorylation. In vitro studies showed enhanced anti-tumour efficacy of GD2 CAR-T cells in combination with alectinib, with synergistic effect becoming evident in sequential coculture models. In vivo, the combination therapy reduced tumour growth, extended survival, and was associated with decreased PD-L1 expression and increased CAR-T cell infiltration.</p> Conclusion <p>Alectinib enhances the efficacy of GD2 CAR-T therapy in ALK-mutant NB primarily by attenuating PD-L1-mediated immune evasion, supporting its potential as a combinatorial therapeutic strategy.</p>

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Alectinib boosts anti-tumor efficacy of disialoganglioside 2 chimeric antigen receptor T cells in ALK-mutated neuroblastoma by suppressing programmed death-ligand 1

  • 期刊论文

  • 发表日期：

    2026年3月23日

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  • Yuya Sugitatsu,
  • Akimasa Tomida,
  • Masaya Suematsu,
  • Tomoya Inoue,
  • Hiroshi Kubo,
  • Yozo Nakazawa,
  • Shigeki Yagyu,
  • Tomoko Iehara

摘要

Background

High-risk ALK-mutant neuroblastoma (NB) presents challenges due to drug resistance and an immunosuppressive tumour microenvironment (TME). Combining molecular targeted therapy with adoptive cell therapy offers a potential therapeutic strategy.

Objective

To investigate the effects of alectinib, an ALK inhibitor, with disialoganglioside 2 (GD2) chimeric antigen receptor T (CAR-T) cell therapy in overcoming immune evasion in ALK-mutant NB.

Methods

Interferon gamma-induced programmed death-ligand 1 (PD-L1) expression and ALK signalling were analysed in ALK-mutant NB cells. The combination of alectinib and GD2 CAR-T cells was assessed in vitro, including sequential co-culture assays, and in vivo in an ALK-mutant xenograft model with multiple treatment arms.

Results

Alectinib suppressed PD-L1 expression by inhibiting ALK downstream pathways, including STAT3 and ERK1/2 phosphorylation. In vitro studies showed enhanced anti-tumour efficacy of GD2 CAR-T cells in combination with alectinib, with synergistic effect becoming evident in sequential coculture models. In vivo, the combination therapy reduced tumour growth, extended survival, and was associated with decreased PD-L1 expression and increased CAR-T cell infiltration.

Conclusion

Alectinib enhances the efficacy of GD2 CAR-T therapy in ALK-mutant NB primarily by attenuating PD-L1-mediated immune evasion, supporting its potential as a combinatorial therapeutic strategy.