The most common primary malignant brain tumor, glioblastoma (GBM) remains uniformly fatal despite surgical resection, radiation therapy and chemotherapy. Moreover, these conventional therapies are associated with considerable mortality and result in incapacitating damage to surrounding normal brain and system tissues. A promising alternative is the use of immunotherapy, which has ts c in phase III clinical trials, leading to pivotal approvals by the FDA of two prototypic immune-based cancer treatments within the past two years. Substantial evidence suggests that T cells, particularly cytotoxic T lymphocytes (CTLs), have the ability to eradicate large, well-established tumors while leaving healthy cells untouched. Bispecific T cell Engagers (BiTEs) represent an emerging class of bispecific antibody that has been shown to effectively redirect T cells against tumor cells. BiTEs promise to overcome many critical barriers that have traditionally limited translation of immunotherapy to the clinic. Separating this platform from other available immunotherapeutic approaches, our preliminary data support that BiTEs are (1) highly-specific molecules that greatly reduce the risk of toxicity, (2) have the ability to penetrate the BBB and accumulate in intracerebral tumors, and (3) may potentially overcome multiple mechanisms of immunosuppression present in patients with GBM. To date, BiTEs have not previously targeted tumor-specific antigens, and until my studies, have not yet been tested for their ability to mediate activity against tumors of the central nervous system (CNS). Here, I design a BiTE against the EGFRvIII tumor-specific antigen and perform preclinical tests to determine its efficacy against EGFRvIII-expressing glioblastoma (GBM). In this proposal, I will determine critical cellular components of a potent BiTE-mediated antitumor response. Furthermore, I explore the possibility that BiTEs convert suppressive, regulatory T cells into immune cells with potent antitumor effector function. This work has the potential to improve the clinical management of patients with GBM by generating a novel therapeutic.

Public Health Relevance

The significance of this research is that it may advance a new therapy for malignant brain tumors as well as provide a strategy for treatment that can be applied to many other cancers. Improved therapy for cancer has significant potential to improve public health and quality of life for patients affected by malignant disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F09-P (21))
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Damico, Mark W
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Duke University
Schools of Medicine
United States
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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
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
Choi, Bryan D; Gedeon, Patrick C; Sanchez-Perez, Luis et al. (2013) Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody. Oncoimmunology 2:e26757
Choi, Bryan D; Gedeon, Patrick C; Kuan, Chien-Tsun et al. (2013) Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis. J Immunol Methods 395:14-20
Choi, Bryan D; Gedeon, Patrick C; Herndon 2nd, James E et al. (2013) Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody. Cancer Immunol Res 1:163
Choi, Bryan D; Fecci, Peter E; Sampson, John H (2012) Regulatory T cells move in when gliomas say ""I Do"". Clin Cancer Res 18:6086-8