Project 1. Targeted Radiotherapy of Neoplastic Meningitis using Monoclonal Antibodies Labeled with Alpha Particle Emitting  At. Michael Zaiutsky, Ph.D., Project Leader Neoplastic meningitis (NM), characterized by the dissemination of malignant tumor cells within the leptomeningeal space and metastatic spread along the brain and spine, is a devestating disease resulting in a median survival of only 2-6 months. In terms of number of patients affected, breast and lung carcinoma are the most common primary sites that metastasize to the leptomeninges. We propose to focus initially on the rapid translational development of a targeted radiotherapeutic for breast carcinoma NM and if successful, apply the same approach to lung carcinoma. Our strategy is to combine trastuzumab with the a-particle emitter ^^^At because these a-particles have a greater cytotoxic effectiveness than conventional radiation and have a range in tissue of only a few cell diameters, characteristics that offer important advantages for NM treatment. We seek to determine the best method for labeling trastuzumab not only forAt but also for  l to move fonward to clinical investigation. If we can establish similar in vivo behavior for mAb labeled via the two radiohalogens, PET imaging with  l-labeled trastuzumab could provide a valuable tool for determining radiation dosimetry, evaluating distribution within the neuroaxis, and individualizing patient treatment protocols for At-labeled trastuzumab.
Our Specific Aims are: 1) To label trastuzumab with At and  l using methodologies designed to minimize dehalogenation and maximize entrapment of radioactivity within tumor cells after labeled mAb internalization;2) to evaluate these radiolabeled trastuzumab conjugates in human breast carcinoma cells in vitro, and tissue distribution in mice with subcutaneous breast carcinoma xenografts and in an athymic rat NM model of HER2 expressing breast carcinoma;3) to determine the therapeutic efficacy, neuroaxis distribution, toxicity, and radiation dosimetry in athymic rat models of NM;4) To obtain FDA Investigational New Drug permits for the best  At- and  l-labeled trastuzumab conjugates, and then to conduct clinical trials in patients with breast carcinoma NM and 5) Using the same translational paradigm determine the best strategy for labeling panitumumab with At and  I and evaluate their potential as targeted radiotherapeutics and diagnostics for patients with lung carcinoma NM.
Neoplastic meningitis is a devastating disease characterized by the spread of malignant tumor cells through-out the cerebrospinal fluid compartment, along the brain and spine, for which there is no effective treatment. Using highly radioactive antibodies, we seek to be able to treat this disease in breast and lung cancer patients without the debilitating side effects that are associated with current therapeutic approaches.
|Desjardins, Annick; Gromeier, Matthias; Herndon 2nd, James E et al. (2018) Recurrent Glioblastoma Treated with Recombinant Poliovirus. N Engl J Med 379:150-161|
|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|
|Chandramohan, Vidyalakshmi; Pegram, Charles N; Piao, Hailan et al. (2017) Production and quality control assessment of a GLP-grade immunotoxin, D2C7-(scdsFv)-PE38KDEL, for a phase I/II clinical trial. Appl Microbiol Biotechnol 101:2747-2766|
|Batich, Kristen A; Reap, Elizabeth A; Archer, Gary E et al. (2017) Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination. Clin Cancer Res 23:1898-1909|
|Chandramohan, Vidyalakshmi; Bryant, Jeffrey D; Piao, Hailan et al. (2017) Validation of an Immunohistochemistry Assay for Detection of CD155, the Poliovirus Receptor, in Malignant Gliomas. Arch Pathol Lab Med 141:1697-1704|
|Yu, Xin; Pegram, Charles N; Bigner, Darell D et al. (2017) Development and validation of a cell-based fluorescent method for measuring antibody affinity. J Immunol Methods 442:49-53|
|Bao, Xuhui; Pastan, Ira; Bigner, Darell D et al. (2016) EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery. Receptors Clin Investig 3:|
|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|
|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|
|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|
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