The NOB has made substantial progress towards building an infrastructure necessary for fulfilling its mission of developing new and improved therapies for children and adults with brain and spinal cord tumors. Since Dr. Gilbert's arrival at the NIH in November 2014, he has rebuilt the Brain Tumor Clinical and Clinical Research Program: a highly collaborative, robust translational research program centered on finding treatments for brain and other central nervous system tumors. In addition to conducting basic and translational research, the NOB has become a nationally recognized resource for patient information and referrals for second opinions. In addition to seeing and treating brain tumor patients, Dr. Gilbert currently runs a significant number of national clinical trials and helps organize and administrate over several large national Neuro-Oncology translational science initiatives. Dr. Gilbert led RTOG 0825 which evaluated the role of the anti-angiogenic agent, bevacizumab, in patients with newly diagnosed glioblastoma in a double-blind placebo controlled randomized phase III trial. This study accrued 973 patients and successfully incorporated upfront stratification by two molecular parameters, as there was 100% compliance with tumor tissue submission. This study, which did not demonstrate a survival benefit for bevacizumab, demonstrated neurocognitive decline and worsened symptom burden and quality of life in the patients treated with bevacizumab. This study was presented at the Plenary Session at ASCO and published in the New England Journal of Medicine. These efforts have led to his leadership of NRG BN002, a clinical trial that is testing the safety of adding the immune checkpoint inhibitors, ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) in patients with newly diagnosed glioblastoma. This is the prelude to a randomized, trial that will determine whether these immune checkpoint inhibitors have efficacy in glioblastoma. A critical component of the trial will be the immunologic monitoring which will comprise testing of tumor tissue for mediators of immune-reactivity and serial monitoring of peripheral blood mononuclear cells as an indicator of the impact of treatment on immune competence. This work has been done in the NOB Lab. In addition, 2 clinical trials have been developed to address important treatment issues. The first will determine the impact of corticosteroids on a patient's ability to mount a T cell response. By collecting blood samples from patients being tapered off corticosteroids, we will determine how long the immune-suppressive effects remain. Conversely, by testing T cells from blood after institution of corticosteroids, we can determine how quickly the immunosuppression occurs and if there is a dose that is low enough to not significantly impact immune function. The second study is designed to determine which patients with newly diagnosed glioblastoma are likely to respond to immune checkpoint therapy. Using a novel tosylactivated bead assay developed in Dr. Gilbert's laboratory, blood samples from patients enrolled to receive immunotherapy will be obtained before treatment then tested to see the level of reactivity to the bead alone and bead plus checkpoint inhibitor. These pretreatment ex vivo responses will be compared with results after patients are treated with the immune checkpoint inhibitors on the clinical trial to determine if the pretreatment assay predicts subsequent response. Dr. Gilbert has also transitioned the Brain Tumor Trials Collaborative (BTTC) from M. D. Anderson Cancer Center. This is a national consortium that was founded on philanthropic support. The mission of the BTTC is to rapidly develop and complete innovative clinical trials for patients with primary brain tumors. To date, the BTTC has completed a study that used a factorial design (8 treatment arms were evaluated simultaneously) and a trial that used an adaptive randomized design (patient allocation based on treatment efficacy using patient by patient rebalancing). This effort is currently being transferred from the M. D. Anderson Cancer Center to the NCI. There are currently 3 active studies and once re-launched, and addition study concepts are anticipated. There are 25 participating sites. The NOB has created a vibrant, robust and clinically busy center for neuro-oncology excellence that serves as a national resource for patients with CNS malignancies (regardless of their ability to pay), for information, consultation, clinical trials or referrals to their local centers of excellence for clinical care and NCI-sponsored trials. This was an important accomplishment because: Part of the mission of the NCI is to provide expertise to patients and physicians for a lethal tumor type not frequently seen in the community and for whom standard treatment options are limited. A busy and robust clinical program ensures a steady flow of patients with primary CNS tumors imperative for stimulating clinical and translational research by ensuring rapid patient accrual to clinical trials, efficient acquisition of tissue for basic and translational research, and for enticing pharmaceutical/biotechnology companies to co-develop novel CNS tumor agents with the NOB and the NCI at large. A multi-disciplinary tumor board convenes every other week and is attended by neuro-oncologists, radiation oncologists, neurosurgeons, neuropathologists and laboratory investigators. Complex and challenging patients are presented and discussed, optimizing individual patient care and leading to many collaborative interactions and research projects. This Tumor Board is complemented by a bi-weekly pathology review where NIH neuropathologists prepare specimens from active clinical patients that are examined microscopically and morphologic and genetic features are discussed in conjunction with members of the Brain Tumor Clinical Team. Additionally, a Molecular Tumor Board has been incorporated into the Pathology Review that reviews all of the available molecular information from individual patient's tumors so that therapies can be considered in the context of this information. Below are partial lists of accomplishments in the building of an NIH-wide multidisciplinary Brain Tumor Clinic with active participation from three different NCI Branches (ROB, MOCRU, CCRLP), five different NIH Institutions (NCI, NINDS, NEI, NHLBI, NIMH), and six different Clinical Center Programs (Neuroradiology, Psychiatry, Pain and Palliation, Rehabilitation Medicine, Social Work). Expertise represented in the clinic includes Medical Oncology, Radiation Oncology, Neurosurgery, Neurology, Ophthalmology, Cardiology, Psychiatry, Endocrinology, Social Work, and Rehabilitation Medicine; Assembled a primary neuro-oncology clinical care/research team, which now consists of 5 neuro-oncologists, 4 NOB-trained neuro-oncology nurse practitioners,5 research nurses, 4 neuro-oncology fellow, 4 clinical collaborators, 3 patient coordinators, 2 clinical trials specialists and 2 data managers; Additionally, the NOB provides neuro-oncology services for Walter Reed Medical Center, in Bethesda; established close collaborative clinical programs with John Hopkins Medical Center, George Washington Medical Center, Fairfax Inova and Washington Hospital Center and a wide array of private neurosurgical, radiation, and oncology practice groups locally and nationally; created a neuro-oncology fellowship training program between the National Institutes of Health and the John Hopkins Medical Center. Since the Brain Tumor Clinical and Clinical Research Program re-initiated in 2015, the NOB launched 15 clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Support Services Intramural Research (ZID)
Project #
1ZIDBC011642-05
Application #
10015117
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Rowe, Lindsay S; Butman, John A; Mackey, Megan et al. (2018) Differentiating pseudoprogression from true progression: analysis of radiographic, biologic, and clinical clues in GBM. J Neurooncol :
Blumenthal, Deborah T; Won, Minhee; Mehta, Minesh P et al. (2018) Short delay in initiation of radiotherapy for patients with glioblastoma-effect of concurrent chemotherapy: a secondary analysis from the NRG Oncology/Radiation Therapy Oncology Group database. Neuro Oncol 20:966-974
Wu, Jing; Frady, Lauren N; Bash, Ryan E et al. (2018) MerTK as a therapeutic target in glioblastoma. Neuro Oncol 20:92-102
Yust Katz, Shlomit; Cachia, David; Kamiya-Matsuoka, Carlos et al. (2018) Ependymomas arising outside of the central nervous system: A case series and literature review. J Clin Neurosci 47:202-207
Yan, F; Thall, P F; Lu, K H et al. (2018) Phase I-II clinical trial design: a state-of-the-art paradigm for dose finding. Ann Oncol 29:694-699
Shi, Wenyin; Scannell Bryan, Molly; Gilbert, Mark R et al. (2018) Investigating the Effect of Reirradiation or Systemic Therapy in Patients With Glioblastoma After Tumor Progression: A Secondary Analysis of NRG Oncology/Radiation Therapy Oncology Group Trial 0525. Int J Radiat Oncol Biol Phys 100:38-44
Feng, Jie; Zhang, Qi; Li, Chuzhong et al. (2018) Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14-3-3? in oncocytomas. J Pathol 245:361-372
Ratnam, Nivedita M; Gilbert, Mark R; Giles, Amber J (2018) Immunotherapy in CNS Cancers: the Role of Immune Cell Trafficking. Neuro Oncol :
Ho, Winson S; Wang, Herui; Maggio, Dominic et al. (2018) Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade. Nat Commun 9:2126
Cavalli, Florence M G; Hübner, Jens-Martin; Sharma, Tanvi et al. (2018) Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol 136:227-237

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