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<p>Many cancers evade immunosurveillance by downregulating surface major histocompatibility class (MHC)-I. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes MHC-I degradation and is elevated in glioma. Evolocumab is a clinically approved PCSK9 inhibitor which restores MHC-I expression in pre-clinical cancer models. However, monoclonal antibodies have limited blood brain/tumor barrier penetrance (BBB/BTB). We conducted a window-of-opportunity trial, evaluating evolocumab’s BBB/BTB penetrance and biological effect (PesKE; NCT04937413). Patients with newly diagnosed or recurrent glioma undergoing a clinically indicated biopsy or resection were enrolled (n = 32, M: 16, F: 16; control average age: 51.85, evolocumab: 53). Intervention participants (n = 6) received a single subcutaneous evolocumab dose pre-procedure, of which 4 provided research tissue. No significant adverse events were observed. Evolocumab was detected in all analyzed intervention tissue, with an average tumor: blood ratio of 0.0222 (SD ± 0.0190), akin to other monoclonals. Evolocumab quantitation was 4.44× greater in contrast-enhancing (mean 0.0068 fmol/mcg (SD ± 0.001)) vs non-contrast enhancing cases (mean 0.0015 fmol/mcg (SD ± 0.0004)). Proteomic analysis found positive trends between evolocumab and MHC-I subtypes (HLA-A-C, E-G), with a significant positive correlation with HLA-H (R<sup>2</sup> = 0.9584, <i>p</i> = 0.021*). Tumor tissue with higher evolocumab titers demonstrated increased surface MHC-I and CD8<sup>+</sup> T cell infiltration. Increased CD8<sup>+</sup> <i>TNF</i>, <i>FASLG</i> and <i>GZMA</i> transcription was observed in high titer tissue compared to low titer tissue and untreated controls. Pre-resection evolocumab is well tolerated but exhibits BBB/BTB penetrance akin to other monoclonal antibodies. Increased tumoral evolocumab/PCSK9i may enhance tumoral MHC-I/effector CD8<sup>+</sup> infiltration. Future work will explore combining evolocumab with BBB/BTB opening therapies like low-intensity focused ultrasound.</p>

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A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8+ infiltration in glioma

  • 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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  • Kirit Singh,
  • Matthew W. Foster,
  • Marlene J. Violette,
  • Anna M. Corcoran,
  • Kelly M. Hotchkiss,
  • Chelsea O. Railton,
  • Emily E. Blandford,
  • Kathryn E. Blethen,
  • Elizabeth L. Thomas,
  • William C. McIntosh,
  • David M. Ashley,
  • Annick Desjardins,
  • Henry S. Friedman,
  • Margaret O. Johnson,
  • Allan Friedman,
  • Stephen Keir,
  • Evan D. Buckley,
  • James E. Herndon,
  • Roger E. McLendon,
  • John H. Sampson,
  • Evan Calabrese,
  • Giselle Y. López,
  • Gerald A. Grant,
  • Anoop P. Patel,
  • Simon G. Gregory,
  • Chuan-Yuan Li,
  • Peter E. Fecci,
  • Mustafa Khasraw

摘要

Many cancers evade immunosurveillance by downregulating surface major histocompatibility class (MHC)-I. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes MHC-I degradation and is elevated in glioma. Evolocumab is a clinically approved PCSK9 inhibitor which restores MHC-I expression in pre-clinical cancer models. However, monoclonal antibodies have limited blood brain/tumor barrier penetrance (BBB/BTB). We conducted a window-of-opportunity trial, evaluating evolocumab’s BBB/BTB penetrance and biological effect (PesKE; NCT04937413). Patients with newly diagnosed or recurrent glioma undergoing a clinically indicated biopsy or resection were enrolled (n = 32, M: 16, F: 16; control average age: 51.85, evolocumab: 53). Intervention participants (n = 6) received a single subcutaneous evolocumab dose pre-procedure, of which 4 provided research tissue. No significant adverse events were observed. Evolocumab was detected in all analyzed intervention tissue, with an average tumor: blood ratio of 0.0222 (SD ± 0.0190), akin to other monoclonals. Evolocumab quantitation was 4.44× greater in contrast-enhancing (mean 0.0068 fmol/mcg (SD ± 0.001)) vs non-contrast enhancing cases (mean 0.0015 fmol/mcg (SD ± 0.0004)). Proteomic analysis found positive trends between evolocumab and MHC-I subtypes (HLA-A-C, E-G), with a significant positive correlation with HLA-H (R2 = 0.9584, p = 0.021*). Tumor tissue with higher evolocumab titers demonstrated increased surface MHC-I and CD8+ T cell infiltration. Increased CD8+ TNF, FASLG and GZMA transcription was observed in high titer tissue compared to low titer tissue and untreated controls. Pre-resection evolocumab is well tolerated but exhibits BBB/BTB penetrance akin to other monoclonal antibodies. Increased tumoral evolocumab/PCSK9i may enhance tumoral MHC-I/effector CD8+ infiltration. Future work will explore combining evolocumab with BBB/BTB opening therapies like low-intensity focused ultrasound.