Project 3: EGFRwt and EGFRvlll Dual-Specific Immunotoxin for Glioblastoma Multiforme Darell D. Bigner, M.D., PhD., Project Leader Glioblastoma multiforme (GBM) is the most common and most malignant primary brain tumor. Median survival remains at 15 to 18 months and recurrence is almost universal despite extensive surgery, external beam radiotherapy and chemotherapy. Basic studies by us and TCGA have shown that EGFRwt and EGFRvlll are the most commonly amplified genes in GBM. We have developed a duals specific high affinity immunotoxin D2C7-(scdsFv)-PE38KDEL (D2C7IT) that avidly kills GBM cells expressing EGFRwt and/or EGFRvlll in vitro and in vivo. Our hypothesis is that treatment of GBM reactive with our dual-specific EGFRwt and EGFRvlll D2C71T construct delivered by CED with catheter placement determined by computer algorithm and delivery monitored by imaging will result in efficacious and minimally toxic treatment of GBM.
Our Specific Aims are: 1) to prepare a GLP clinical batch of at least 250 mgm of D2C7IT;to perform all efficacy, toxicity, potency, sterility and stability studies;and to obtain an FDA IND for D2C7IT;2) to conduct a Phase I dose-escalation study of D2C71T of recurrent GBM patients whose tumors react with D2C7. EGFRwt and EGFRvlll amplification and expression will be conducted by fluorescence in situ hybridization (FISH) quantitative PCR and immunohistochemistry. CED with computer algorithm catheter placement and delivery imaging by  l-labeled albumin PET and co- CED-infused gadolinium-DTPA MRI will be performed; 3) at the Phase 1 MTD, to conduct a single arm Phase 11 study of recurrent GBM patients who have failed standard of care and bevacizumab compared to a similar historical control arm.
GBM is the most common and malignant primary brain tumor. Despite current treatments of surgery, radiation and chemotherapy, recurrence is almost universal and there are very few long-term survivors. We are proposing a new treatment with a potent bacterial toxin guided to GBM cells by a protein reactive with GBM cells.
|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|
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|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|
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