This is an application to the NCI from a group of senior scientists and physician/scientists with a long history of collaboration who proposes novel approaches for treatment of two of the conditions in neuro-oncology which are most refractory to treatment, neoplastic meningitis (NM) and glioblastoma multiforme (GBM). NM is characterized by the dissemination of malignant tumor cells within the leptomeningeal space and metastatic spread through the cerebrospinal fluid along the brain and spine. NM from carcinoma of the breast and lung are the most common subtypes. Prognosis of NM is grim with median survival of 2 to 6 months. Current therapy is ineffective and limited by toxicity to the CNS. GBM is the most common and most malignant primary brain tumor. Despite hundreds of clinical trials, only two agents, temozolomide and bevacizumab, have been approved for treatment by the FDA in the last decade. Less than half of patients treated with these two agents respond. Recurrence after treatment is almost universal and median survival is 15 to 18 months with few long-term survivors. Targeted immunotherapy with monoclonal antibodies (MAbs) or their fragments armed with Astatine 211 or Pseudomonas exotoxin for the treatment of NM or GBM is proposed in Projects 1 and 3. In Project 2 vaccine approaches against the ubiquitous antigens from CMV in GBM are proposed to be improved by decreasing immunosuppressive regulatory T-cells or TReg in the setting of temozolomide-induced lymphopenia by administering a specific humanized MAb reactive with the IL-2Ra receptor. Project 1, led by Michael Zaiutsky, is entitled """"""""Targeted Radiotherapy of Neoplastic Meningitis using Monoclonal Antibodies Labeled with Alpha Particle Emitting At."""""""" Project 2, led by John Sampson, and is entitled, """"""""Targeting Immunosuppression Pathways to Enhance Brain Tumor Immunotherapy."""""""" Project 3, led by Darell Bigner, and is entitled, """"""""EGFRwt and EGFRvlll Dual-Specific Immunotoxin for Glioblastoma Multiforme."""""""" These three projects will be supported by an Imaging Core, Daniel Barboriak, Core Director;a Clinical Support Core for biostatistics, informatics, immune monitoring, and a brain tumor tissue biorepository, James Vredenburgh, Core Director;and an Administrative Core, Darell Bigner, Core Director.

Public Health Relevance

Two of the conditions in neuro-oncology that are most refractory to treatment are neoplastic meningitis (NM) and glioblastoma multiforme (GBM). NM from carcinoma of the breast and lung are the most common subtypes, with a median survival of 2-6 months. GBM is the most common and most malignant primary brain tumor, with median survival at recurrence being 15-18 months. This application proposes novel targeted approaches for treatment of these two very refractory conditions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-P (O1))
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Timmer, William C
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Duke University
Schools of Medicine
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Desjardins, Annick; Gromeier, Matthias; Herndon 2nd, James E et al. (2018) Recurrent Glioblastoma Treated with Recombinant Poliovirus. N Engl J Med 379:150-161
Atik, Ahmet F; Suryadevara, Carter M; Schweller, Ryan M et al. (2018) Hyaluronic acid based low viscosity hydrogel as a novel carrier for Convection Enhanced Delivery of CAR T cells. J Clin Neurosci 56:163-168
Chandramohan, Vidyalakshmi; Pegram, Charles N; Piao, Hailan et al. (2017) Production and quality control assessment of a GLP-grade immunotoxin, D2C7-(scdsFv)-PE38KDEL, for a phase I/II clinical trial. Appl Microbiol Biotechnol 101:2747-2766
Batich, Kristen A; Reap, Elizabeth A; Archer, Gary E et al. (2017) Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination. Clin Cancer Res 23:1898-1909
Chandramohan, Vidyalakshmi; Bryant, Jeffrey D; Piao, Hailan et al. (2017) Validation of an Immunohistochemistry Assay for Detection of CD155, the Poliovirus Receptor, in Malignant Gliomas. Arch Pathol Lab Med 141:1697-1704
Yu, Xin; Pegram, Charles N; Bigner, Darell D et al. (2017) Development and validation of a cell-based fluorescent method for measuring antibody affinity. J Immunol Methods 442:49-53
Bao, Xuhui; Pastan, Ira; Bigner, Darell D et al. (2016) EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery. Receptors Clin Investig 3:
Saraswathula, Anirudh; Reap, Elizabeth A; Choi, Bryan D et al. (2016) Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy. Cancer Immunol Immunother 65:205-11
Suryadevara, Carter M; Riccione, Katherine A; Sampson, John H (2016) Immunotherapy Gone Viral: Bortezomib and oHSV Enhance Antitumor NK-Cell Activity. Clin Cancer Res 22:5164-5166
Bao, Xuhui; Chandramohan, Vidyalakshmi; Reynolds, Randall P et al. (2016) Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats. Invest New Drugs 34:149-58

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