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Targeted Alpha-Particle Radiotheraphy of Brain Tumors with 211At-81C6 Antibody

使用 211At-81C6 抗体对脑肿瘤进行靶向α粒子放射治疗

基本信息

批准号：
8805239
负责人：
Michael Rod Zalutsky
金额：
$ 33.15万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8805239
关键词：
Adult Adverse effects Alpha Particles Antibodies Astatine Biological Brain Brain Neoplasms Bystander Effect Caliber Cells Characteristics Chemistry Child Clinical Clinical Trials Combined Modality Therapy Diffusion Disease Dose Drug Formulations Effectiveness External Beam Radiation Therapy Extracellular Matrix Failure Glioblastoma Glycoproteins Goals Half-Life Human Injection of therapeutic agent Investigation Kinetics Label Location Long-Term Survivors Malignant - descriptor Malignant Glioma Malignant neoplasm of brain Maximum Tolerated Dose Minor Monoclonal Antibodies Monoclonal Antibody 81C6 Neurocognitive Newly Diagnosed Normal tissue morphology Outcome Patients Phase Phase I Clinical Trials Pilot Projects Play Primary Brain Neoplasms Procedures Quality of life Radiation Radiation therapy Radioactivity Radiochemistry Radioisotopes Radiolabeled Reagent Recommendation Recurrence Resistance Role Series Site Solutions Surgically-Created Resection Cavity Tenascin Therapeutic Therapeutic Effect Time Tin Tissues Toxic effect Variant base bevacizumab conventional therapy cytotoxic cytotoxicity expectation improved novel strategies particle phase 1 study phase 2 study pre-clinical radiotracer research clinical testing response temozolomide therapeutic effectiveness tumor tumor growth tumor progression tumor specificity

项目摘要

Current approaches for the treatment of primary malignant glioma (GBM) are largely unsuccessful, with most GBM recurring at or adjacent to their site of origin, indicating a failure to eradicate local tumor growth; moreover, these treatments lack tumor specificity, frequently inducing normal brain toxicity, resulting in decline in quality of life. Our hypothesis is that these limitations can be overcome by combining a GBM reactive monoclonal antibody (MAb) with a radionuclide emitting highly cytotoxic and focal radiation. Our clinical goal is to evaluate the therapeutic potential of 211At-labeled anti-tenascin MAb 81C6 in newly diagnosed GBM patients. Astatine-211 emits ¿-particles that have a greater cytotoxic effectiveness and are less susceptible to resistance than conventional radiation, and have a range in tissue of only a few cell diameters, characteristics that can offer important advantages for brain tumor treatment. In our pilot study performed with chimeric 81C6 (ch81C6) labeled via N-succinimidyl 3-[211At]astatobenzoate (SAB) in recurrent brain tumor patients, encouraging responses were obtained with minimal toxicity, with 2 GBM patients surviving for nearly 3 years. However, the maximum tolerated dose was not determined because of radiolysis-induced problems with 211At labeling at higher activity levels. Basic radiochemistry investigations over the past few years have now yielded a solution to this problem. In parallel, our preclinical goal is to lay the groundwork for eventual clinical evaluation of 211At-labeled ch81C6 combined with MAb labeled with a low-energy ¿-emitter to extend the zone of therapeutic effectiveness beyond the SCRC interface. Our Specific Aims are: 1) To complete radiochemistry studies optimizing labeling of ch81C6 with 211At at the activity levels needed for reliable dose escalation; 2) to conduct a Phase I/II clinical trial of 211At-labeled ch81C6 administered into the SCRC of newly diagnosed GBM patients, with the Phase 1 study done at escalating doses of 211At (mCi) and the Phase II dose at a targeted radiation dose (Gy) to the SCRC margins; 3) to evaluate efficacy and normal tissue toxicity of an anti-tenascin 81C6 combination therapy approach utilizing the ¿-particle emitter 211At and either the ¿-particle emitter 177Lu or 131I.

目前治疗原发性恶性胶质瘤（GBM）的方法在很大程度上是不成功的