Project 3. Translational Clinical Trials for Primary CMSTumors. David A. Reardon, M.D., Project Leader Despite standard post-surgical cytotoxic radiotherapy and chemotherapy, the outcome for patients with primary brain tumors remains dismal. To overcome the limitations of conventional approaches, we have developed innovative therapeutics including a peptide vaccine against the tumor-specific EGFRvlll mutant receptor and a regionally administered, radiolabeled anti-tenascin monoclonal antibody, that have each advanced to multi-center, randomized phase III studies based on highly encouraging improved survival and minimal toxicity observed in clinical trials conducted at our center. In this application, we will further advance these approaches by expanding our immunotherapy program to: evaluate dose intensive temozolomide or bevacizumab to enhance EGFRvlll vaccine immunogenicity;evaluate our EGFRvlll vaccine among patients with non-resectable tumors;and evaluate a novel brain tumor stem cell RNA-pulsed dendritic cell vaccination strategy. We will also evaluate several tumor-specific MAb immunotoxin constructs developed and extensively evaluated preclinically at our center that target EGFRvlll (MR1-1;BB-IND# 12589), wild-type EGFR and EGFRvlll (D2C7), glycoprotein non-metastatic B (F6V), gangliosides 3'-isoLM1 and 3'6'-isoLD1, and chondroitin proteoglycan sulfate (Me1-14, Me1-5, and 9.2.27), respectively. We will also evaluate three novel, regionally administered therapeutic strategies including Auger electron-labeled modular recombinant transporters (MRT) against EGFR (Project 1), a recombinant poliovirus/rhinovirus construct produced through the NCI RAID program, and a novel balloon catheter device for convection enhanced delivery (CED). Finally, we will also investigate potential limitations of CED by co-infusing a radiolabeled high molecular weight marker such as 124l-albumin imaged by positron emission tomography. We hypothesize that innovative therapeutics, appropriate clinical trial eligibility, rigorous target validation, and enhanced delivery strategies will improve overall survival and quality of life for patients with malignant glioma.
Our Specific Aims are: 1. To conduct Phase I and II clinical trials to assess whether innovative therapeutics including vaccine immunotherapy strategies, novel immunotoxins, modular recombinant transporters and genetically modified poliovirus, can improve overall survival and quality of life for malignant glioma patients; 2. To conduct Phase I and II clinical trials designed to determine whether enhanced local delivery of novel therapeutics can be achieved in order to improve overall survival and quality of life for malignant glioma patients.
The clinical investigation studies in Project 3 are all designed to develop more effective and less toxic treatments for malignant brain tumors.
|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|
|Slastnikova, Tatiana A; Rosenkranz, Andrey A; Zalutsky, Michael R et al. (2015) Modular nanotransporters for targeted intracellular delivery of drugs: folate receptors as potential targets. Curr Pharm Des 21:1227-38|
|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|
|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|
|Koumarianou, Eftychia; Slastnikova, Tatiana A; Pruszynski, Marek et al. (2014) Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter--a potential Auger electron emitting EGFR-targeted radiotherapeutic. Nucl Med Biol 41:441-9|
|Choi, Bryan D; Suryadevara, Carter M; Gedeon, Patrick C et al. (2014) Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma. J Clin Neurosci 21:189-90|
|Brown, Michael C; Dobrikova, Elena Y; Dobrikov, Mikhail I et al. (2014) Oncolytic polio virotherapy of cancer. Cancer 120:3277-86|
|Miao, Hongsheng; Choi, Bryan D; Suryadevara, Carter M et al. (2014) EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. PLoS One 9:e94281|
|Killela, Patrick J; Pirozzi, Christopher J; Healy, Patrick et al. (2014) Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas. Oncotarget 5:1515-25|
|Lathia, Justin D; Li, Meizhang; Sinyuk, Maksim et al. (2014) High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor. Cell Rep 6:117-29|
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