Translational Clinical Trials in Neuro-Oncology

原发恶性脑瘤患者的结局仍然令人沮丧。大多数进展发生在原发部位，尽管有传统的手术和放射治疗/化疗。因此，地方控制是改善结果的关键第一步。除了这些肿瘤造成的浸润性破坏外，目前的治疗方法的非特异性不可避免地会导致正常的脑损伤，进一步的临床衰退和生活质量的降低。为了应对恶性脑肿瘤患者对有效、创新疗法的迫切需求，我们中心开发了针对肿瘤相关分子靶点的新疗法，包括手无寸铁的、放射性标记的和毒素结合的单抗(MAbs)。 单抗片段和生长因子配体-毒素结合物。在之前的SRC赠款期间，我们使用放射性标记的单抗、单抗片段和毒素结合物进行的I期和II期临床试验证实，这种疗法是有效的，并且对恶性胶质瘤和肿瘤性脑膜炎的毒性有限。除了实现局部控制的目标外，我们还完成了广泛的临床前和临床研究，以改进系统治疗，例如克服烷基鸟嘌呤转移酶(AGT)介导的化疗耐药，最终到达整个神经轴的所有肿瘤细胞。我们的假设是，针对分子靶点的新疗法将改善局部肿瘤控制，当与更有效的全身治疗相结合时，最终有助于在保留肿瘤细胞的同时消除全部肿瘤细胞。 恶性脑瘤患者的生活质量。这项建议的具体目的是：1)进行第一阶段和第二阶段临床试验，以评估以下药物的抗肿瘤活性和毒性：1)针对EGFRvIII、GPNMB、MRP3和胶质瘤相关神经节苷脂3‘-isLM1和3’，6‘-isLD1的新开发的肿瘤靶向治疗药物；2)钚-177的放射免疫治疗；3)溶瘤性脊髓灰质炎/鼻病毒重组；以及4)BCNU诱导的DNA链间和交联修复的抑制剂。 具体目的2.确定在本项目的临床试验中评估的治疗方法对生活质量的影响。

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.