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.
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.
|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|
|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|
|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|
|Mitchell, Duane A; Batich, Kristen A; Gunn, Michael D et al. (2015) Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519:366-9|
|PruszyÅ„ski, Marek; Åyczko, Monika; Bilewicz, Aleksander et al. (2015) Stability and in vivo behavior of Rh[16aneS4-diol]211 at complex: a potential precursor for astatine radiopharmaceuticals. Nucl Med Biol 42:439-45|
|Huang, Dong-Sheng; Wang, Zhaohui; He, Xu-Jun et al. (2015) Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer 51:969-76|
|Pruszynski, Marek; Koumarianou, Eftychia; Vaidyanathan, Ganesan et al. (2015) D-Amino acid peptide residualizing agents bearing N-hydroxysuccinimido- and maleimido-functional groups and their application for trastuzumab radioiodination. Nucl Med Biol 42:19-27|
|Pruszynski, Marek; Koumarianou, Eftychia; Vaidyanathan, Ganesan et al. (2014) Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling. J Nucl Med 55:650-6|
|Choi, Jaeyeon; Vaidyanathan, Ganesan; Koumarianou, Eftychia et al. (2014) N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: influence of isomeric substitution on radiolabeling and target cell residualization. Nucl Med Biol 41:802-12|
|Congdon, Kendra L; Gedeon, Patrick C; Suryadevara, Carter M et al. (2014) Epidermal growth factor receptor and variant III targeted immunotherapy. Neuro Oncol 16 Suppl 8:viii20-5|
Showing the most recent 10 out of 19 publications