Neoplastic meningitis can result from leptomeningeal dissemination of a variety of cancers, either arising from the central nervous system or resulting from invasion by lymphoid neoplasms, carcinoma or melanoma. The hypothesis of this proposal is: that direct intrathecal administration of the I131 labelled monoclonal antibodies or F(ab')2 fragments of Me1-14, B72.3, 181.4, 81C6, 2A6, and other anti-ganglioside, anti-protein or anti-receptor monoclonal antibodies under production in Project 1, and shown to be efficacious and non-toxic in human xenograft models in Projects IIb and IIc, will facilitate specific delivery of therapeutic dosages of radiation to neoplastic tissue with relative sparing of uninvolved neural tissue.
The specific aims of this proposal are: 1) To conduct a series of phase I/II studies with administration by Ommaya reservoir of initially 40 mCi I131, 10 mg protein of the Mabs or their fragments listed above (employing an escalating dosage of radioisotope with a fixed quantity of protein) to patients with recurrent malignancies (particularly medulloblastoma, glioma, ependymoma, pinealoblastoma, carcinoma, and melanoma) metastatic to the subarachnoid spaces with determination of: a) pharmacokinetics of these radiolabeled monoclonal antibodies in CSF and plasma; b) dynamics of normal tissue uptake (including brain and neuraxis) by external gamma camera imaging. 2) To define the toxicity of intrathecal administration of these radiolabeled monoclonal antibodies to patients with recurrent leptomeningeal neoplasms treated in a series of phase I/II studies. 3) To define the therapeutic response associated with intrathecal administration of these radiolabeled monoclonal antibodies to patients with recurrent leptomeningeal neoplasms treated in a series of phase I/II studies. 4) To conduct a series of phase II studies with the Mabs from Aim 1 shown to be non-toxic and efficacious by administering by Ommaya reservoir radiolabeled Mabs to patients with recurrent leptomeningeal neoplasms, allowing definition of: a) toxicity, b) therapeutic response.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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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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