CTIM-10 - A surgical window-of-opportunity clinical trial evaluating the PCSK9 inhibitor Evolocumab in patients with glioma

Friday, November 17, 2023

7:30 PM – 9:30 PM PT

Location: Exhibit Hall A/B

Author(s)

Kirit Singh

Duke Brain Tumor Immunotherapy Program
Durham, North Carolina, United States

Poster Presenter(s)

Kelly M. Hotchkiss

Duke University
Durham, North Carolina, United States

Author(s)

MF

Matthew W. Foster

Duke Proteomics and Metabolomics core
Durham, United States
Chelsea Railton

Duke Brain Tumor Immunotherapy Program
Durham, United States
EB

Emily Blandford

Duke University
Durham, United States
ET

Elizabeth Thomas

Duke University Brain Tumor Biorepository
Durham, United States
EM

Elizabeth S. S. Miller

Duke University School of Medicine, The Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery
Durham, North Carolina, United States
David M. Ashley

The Preston Robert Tisch Brain Tumor Center
Durham, North Carolina, United States
Annick Desjardins

Duke University
Durham, North Carolina, United States
HF

Henry S. Friedman

The Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery
Durham, North Carolina, United States
Margaret O. O. Johnson

Duke University School of Medicine, The Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery
Durham, North Carolina, United States
AF

Allan H. Friedman

Department of Neurosurgery, Duke University
Durham, North Carolina, United States
SK

Steve T. Keir

Duke University School of Medicine
Durham, North Carolina, United States
JH

James E. Herndon, II

Duke Cancer Institute, Department of Biostatistics
Durham, North Carolina, United States
John H. Sampson

Duke University
Durham, North Carolina, United States
CL

Chuan-Yuan Li

Duke Cancer Institute
Durham, United States
Peter E. Fecci

Duke University Department of Neurosurgery
Durham, North Carolina, United States
AP

Anoop Patel

Department of Neurosurgery, Duke University
Durham, North Carolina, United States
Mustafa Khasraw

Duke Cancer Institute
Durham, North Carolina, United States

Gliomas evade the immune system by downregulating cell surface expression of major histocompatibility class (MHC)-I. Antagonism of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases MHC-I expression and can enhance checkpoint inhibition in vivo. Evolocumab is an FDA approved monoclonal antibody (mAb) for hyperlipidemia that inhibits PCSK9. However, large constructs such as mAbs typically have limited penetrance across the blood-brain-barrier. We report the preliminary results of a surgical window-of-opportunity study evaluating if Evolocumab administered subcutaneously pre-preoperatively is detectable in tumor tissue from patients with newly diagnosed or recurrent glioma (PESKe; NCT04937413). Twenty contemporaneous control samples are prospectively collected from patients undergoing craniotomy without receiving Evolocumab. Although non-randomized, these specimens provide valuable information for exploratory comparison of the treated and untreated specimens in terms of drug penetrance and MHC-I expression. To date, 24 patients have been enrolled (M: 14, F: 10) with a median age of 46.5. Of these, 5 received pre-procedure subcutaneous Evolocumab (420mg), while the remaining 19 were analyzed as controls. In treated patients, Evolocumab was detectable via mass spectroscopy (LC-MS/MS) in all analyzed cases, including in tumor tissue from both contrast-enhancing and non-contrast-enhancing regions. Ratios of drug in tumor relative to intra-operative blood were markedly higher in samples from contrast-enhancing regions compared to non-contrast enhancing regions (median ratio of tumor to blood of 0.1503 vs 0.0248 respectively). The tumor proteome was also analyzed using LC-MS/MS to quantitate MHC-I and MHC-II proteins. Initial analysis found increased MHC-I (HLA-A, HLA-B, HLA-C) quantitation via mass spectroscopic analysis of the tumor proteome in treated samples compared to contemporaneous untreated controls. No significant adverse events have been reported in those who received pre-procedure Evolocumab. Ongoing analyses will seek to determine whether increased MHC-I quantities in tumor correspond with increased cell surface expression via immunofluorescence and immunohistochemistry.