RESEARCH—HUMAN—STUDY PROTOCOLS Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade John Lynes, MD * ‡ Sadhana Jackson, MD § Victoria Sanchez, BS * Gifty Dominah, BA * Xiang Wang, MS * Averie Kuek, MS * Christina Piper Hayes, MSN, CRNP * Sarah Benzo, BSN, RN * Gretchen C. Scott, BSN, RN * Prashant Chittiboina, MD, MPH * Kareem A. Zaghloul, MD, PhD * Deric M. Park, MD § Jing Wu, MD, PhD § Christopher S. Hourigan, MD, DPhil ¶ Amber J. Giles, PhD § Tianxia Wu, PhD || Dragan Maric, PhD # Jinguo Chen, MD ** Martha Quezado, MD ‡‡ John D. Heiss, MD * Mark R. Gilbert, MD § Edjah K. Nduom, MD * * Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; ‡ Medstar Georgetown University Hospital, Washington, District of Columbia; § Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; ¶ National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; || Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; # Flow and Imaging Cytometry Core Facility, National Institute of Neurological Diseases and Stroke, Bethesda, Maryland; ** Center for Human Immunology, Autoimmunity, and Infammation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; ‡‡ Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Correspondence: Edjah K. Nduom, MD, National Institutes of Health Clinical Center, Surgical Neurology Branch, Room 3D-20, 10 Center Drive, Bethesda, MD 20814. E-mail: edjah.nduom@nih.gov Received, June 12, 2018. Accepted, July 24, 2018. Published Online, September 4, 2018. Published by Oxford University Press on behalf of Congress of Neurological Surgeons 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. BACKGROUND: Glioblastoma is the most common primary malignancy of the brain, with a dismal prognosis. Immunomodulation via checkpoint inhibition has provided encour- aging results in non-CNS malignancies, but prediction of responders has proven to be challenging in glioblastoma patients. OBJECTIVE: To determine the proportion of patients who have a measurable increase of interferon gamma levels in brain tumor tissue after their frst dose of nivolumab, and to evaluate the safety of using brain tumor microdialysis to monitor for immune response while evaluating the safety of the combination of anti-programmed death 1 (PD-1) and anti- lymphocyte activation gene 3 (LAG-3) checkpoint inhibition. METHODS: The study design is a single-center, nonrandomized phase 1 clinical trial. Up to 15 adult patients with recurrent glioblastoma will be enrolled with the goal of 10 patients completing the trial over an anticipated 18 mo. Patients will undergo biopsy; placement of microdialysis catheters and lumbar drains; treatment with anti-PD-1 checkpoint inhibition; comprehensive immune biomarker collection; tumor resection; and then treatment with anti-PD-1 and anti-LAG-3 checkpoint inhibition until progression. EXPECTED OUTCOMES: We expect interferon gamma levels to increase in the brain as measured via microdialysis in treated patients. Based on published reports, microdialysis in this patient population is expected to be safe, and anti-LAG-3 and anti-PD-1 combined will likely have a similar side efect profle to other checkpoint inhibitor combinations. DISCUSSION: The failure of recent trials of immune therapies in glioblastoma underscores the need to appropriately measure response in the treated tissue. This trial may provide insight on indicators of which patients will respond to immune therapy. KEY WORDS: Glioblastoma, Nivolumab, Microdialysis, Brain neoplasms, Biomarkers, Immunotherapy, Neuro- oncology Neurosurgery 84:945–953, 2019 DOI:10.1093/neuros/nyy392 www.neurosurgery-online.com GENERAL INFORMATION Title: Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade. Study Dates: April 2018 to present. Sponsor/Funding Agency: Intramural Research Program of the National Institute of Neuro- logical Disorders and Stroke. ABBREVIATIONS: CRO, Contract Research Organi- zation; CSF, cerebral spinal fuid; IFNg, interferon gamma; IRB, Institutional Review Board; LAG-3, lymphocyte activation gene 3; PD-1, programmed death 1; PD-L1, programmed death ligand 1 Avindra Nath, MD, Office of the Clinical Director, 10 Center Dr, 10/7C103, Bethesda, MD 20892. Bristol-Myers Squibb (drug only support)– Bristol-Myers Squibb may review any manuscript prior to publication to ensure that it contains no violations of confidentiality and protects relevant intellectual property. Center for Human Immunology, Autoimmunity, and Inflammation. Registry: Clinicaltrials.gov: NCT03493932 (Registration Date: April 11, 2018). Institutional Approvals: National Insti- tutes of Health Combined Neurosciences Internal NEUROSURGERY VOLUME 84 | NUMBER 4 | APRIL 2019 | 945 Downloaded from https://academic.oup.com/neurosurgery/article-abstract/84/4/945/5090739 by guest on 21 May 2020