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<p>Small molecule inhibitors designed to specifically target oncogenic proteins have demonstrated potent anti-tumour activities due to direct effects on tumour cells survival and/or proliferation. However, the effects of these compounds on normal cells, specifically immune cells and their potential to impede or enhance anti-cancer immunotherapies has yet to be fully explored. Using an in vitro co-culture system to assess CD8+ T cell killing of tumour cells, we identified compounds that inhibit Bcl-2 and Bcl-xl as agents that can induce tumour cell death without impacting the differentiation or function of anti-tumour T cells. Accordingly, in vivo treatment of mice bearing solid tumours with a combination of the Bcl-2/Bcl-xl inhibitor AZD0466 and anti-PD-L1 immunotherapy resulted in enhanced anti-tumour effects and improved survival compared to equivalent monotherapies.</p>

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Dual Bcl-2/Bcl-xl inhibition via AZD0466 combines with immune checkpoint blockade to enhance anti-tumour activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月6日

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  • Dane M. Newman,
  • Courtney L. Andersen,
  • Leonie A. Cluse,
  • Andrea Newbold,
  • Peter Fraser,
  • Benjamin W. C. Legg,
  • Luyao Kevin Xu,
  • Deanna A. Mele,
  • Ricky W. Johnstone

摘要

Small molecule inhibitors designed to specifically target oncogenic proteins have demonstrated potent anti-tumour activities due to direct effects on tumour cells survival and/or proliferation. However, the effects of these compounds on normal cells, specifically immune cells and their potential to impede or enhance anti-cancer immunotherapies has yet to be fully explored. Using an in vitro co-culture system to assess CD8+ T cell killing of tumour cells, we identified compounds that inhibit Bcl-2 and Bcl-xl as agents that can induce tumour cell death without impacting the differentiation or function of anti-tumour T cells. Accordingly, in vivo treatment of mice bearing solid tumours with a combination of the Bcl-2/Bcl-xl inhibitor AZD0466 and anti-PD-L1 immunotherapy resulted in enhanced anti-tumour effects and improved survival compared to equivalent monotherapies.