Glioblastoma (GBM) remains uniformly lethal. It is also the most common of the primary malignant brain tumors, which are the most frequent cause of cancer death in children and young adults. In contrast to current therapy which is limited by off-target toxicity, immunotherapy promises an exquisitely precise approach, and substantial evidence indicates that, if appropriately redirected, T cells can eradicate large, well established tumors. We have developed a novel bispecific T cell engager (BiTE) that effectively tethers CD3+ T cells to the surface of tumor cells that express the tumor-specific epidermal growth factor receptor mutation, EGFRvIII. Our first EGFRvIII-CD3 BiTE eradicated well-established EGFRvIIIPOS human GBM in a xenograft model reconstituted with human T cells without evidence of autoimmune toxicity. Based on these data, we developed a developed a EGFRvIII-CD3 BiTE from fully-human antibody segments, increasing clinical safety by drastically reducing the potential for immunogenicity. Because all available antibodies specific for human CD3 do not cross-react with any other species including primates, we have rederived a unique, pharmacologically responsive, immunocompetent, human CD3 transgenic murine model that will allow for direct assessment of the humanized BiTE destine for clinical trial, drastically increasing the validity and translatability of pre-clinical efficacy and toxicity studis. Our overall goal is to translate the BiTE therapeutic platform for safe, effective immunotherapy in patients with EGFRvIII-expressing GBM. In this proposal, we seek to perform Investigational New Drug (IND) required experiments, as the Food and Drug Administration (FDA) has outlined to us in our formal Pre-IND meeting. The in vitro cytoxicity and in vivo efficacy of the lead human construct, shown to bind to both targets, will be validated in Aim 1.
Aim 2 will complete the necessary optimization of protocols for current good manufacturing practice (cGMP) production of the lead human construct and will yield a sufficient quantity for IND-enabling studies.
Aim 3 will document the activity and pharmacokinetics of the cGMP drug product, producing information critical in determining the first-in-man dose. Formal toxicology and stability testing will be completed in Aim 4, allowing for assessment of any potential off-target activity and guiding manufacturing timelines for clinical trial respectively. The sum total of data generated in this proposal, as requested by the FDA during our Pre-IND meeting, will be used to assemble the necessary documents and file an IND application with the FDA in Aim 5.

Public Health Relevance

Glioblastoma (GBM) is uniformly lethal; it is also the most common malignant primary brain tumor. Current therapy is incapacitating and limited by non-specific toxicity to systemic tissue or surrounding eloquent brain. We have developed a method to specifically target GBM using a tumor-specific, bispecific T cell engager that redirects patients' own T cells to recognize and destroy tumors, which has significant potential to improve public health and quality of life for patients affected by GBM and other cancers.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Boshoff, Chris
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Duke University
Schools of Medicine
United States
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Gedeon, Patrick C; Schaller, Teilo H; Chitneni, Satish K et al. (2018) A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma. Clin Cancer Res 24:3611-3631
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
Schaller, Teilo H; Sampson, John H (2017) Advances and challenges: dendritic cell vaccination strategies for glioblastoma. Expert Rev Vaccines 16:27-36
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