Translational Clinical Trials in Neuro-Oncology

原发性恶性脑肿瘤患者的预后仍然令人沮丧。大多数进展发生在原发部位，尽管常规手术和放疗+/-化疗。因此，局部控制是改善结果的关键第一步。除了这些肿瘤引起的浸润性破坏外，当前治疗的非特异性不可避免地导致正常脑损伤，进一步的临床衰退和生活质量下降。为了满足恶性脑肿瘤患者对有效、创新治疗方法的迫切需求，我们中心开发了针对肿瘤相关分子靶点的新型治疗方法，包括非武装、放射性标记和毒素偶联单克隆抗体（mab），

The outcome for patients with primary malignant brain tumors remains dismal. Most progression occurs at the primary site despite conventional surgery and radiation therapy +/- chemotherapy. Therefore local control is the critical first step to improve outcome. In addition to the infiltrating destruction caused by these tumors, the non-specific nature of current therapies inevitably contributes to normal brain injury, further clinical decline and compromised quality of life. In response to the dire need for effective, innovative therapies for patients for malignant brain tumors, our center has developed novel therapeutics aimed at tumor-associated molecular targets, including unarmed, radiolabeled and toxin-conjugated monoclonal antibodies (MAbs), MAb fragments and growth factor ligand-toxin conjugates. During the prior SRC grant period, our Phase I and II clinical trials with radiolabeled MAbs, MAb fragments, and toxin conjugates confirmed that such therapeutics are effective and were associated with limited toxicity for both malignant glioma and neoplastic meningitis. Coupled with our goal of achieving local control, we have also completed extensive preclinical and clinical studies to improve systemic therapies, such as overcoming alkylguanine transferase (AGT)-mediated chemoresistance, to ultimately reach all tumor cells throughout the neuraxis. Our HYPOTHESIS is that novel therapeutics aimed at molecular targets will improve local tumor control and when coupled with more effective systemic therapies, ultimately contribute to overall tumor cell eradication while preserving quality of life for patients with malignant brain tumors. The SPECIFIC AIMS of this proposal are: Specific Aim 1. To conduct Phase I and II clinical trials to assess anti-tumor activity and toxicity of: 1) newly developed, tumor-targeted therapeutics against EGFRvIII, GPNMB, MRP3, and the glioma-associated gangliosides 3'-isoLM1 and 3',6'-isoLD1; 2) radioimmunotherapy with lutetium-177; 3) an oncolytic polio/rhinovirus recombinant; and 4) inhibitors of BCNU-induced DNA interstrand crosslink repair. Specific Aim 2. To determine the impact on quality of life of therapeutics evaluated in clinical trials of this project.