Translational Clinical Trials in Neuro-Oncology

原发性恶性脑肿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，目前治疗的非特异性性质不可避免地导致正常脑损伤，进一步的临床下降和生活质量的降低。针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型疗法，包括非武装、放射性标记和毒素缀合的单克隆抗体（MAb）， 单克隆抗体片段和生长因子配体-毒素缀合物。在之前的SRC资助期间，我们使用放射性标记的单克隆抗体、单克隆抗体片段和毒素缀合物进行的I期和II期临床试验证实，这些治疗方法是有效的，并且与恶性胶质瘤和肿瘤性脑膜炎的有限毒性相关。结合我们实现局部控制的目标，我们还完成了广泛的临床前和临床研究，以改善全身治疗，例如克服烷基鸟嘌呤转移酶（AGT）介导的化疗耐药性，最终达到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，最终有助于整体肿瘤细胞根除，同时保留 恶性脑肿瘤患者的生活质量。该提案的具体目标是：具体目标1。进行I期和II期临床试验，以评估以下药物的抗肿瘤活性和毒性：1）针对EGFRvIII、GPNMB、MRP 3和神经胶质瘤相关神经节苷脂3 '-isoLM 1和3'，6 '-isoLD 1的新开发的肿瘤靶向疗法; 2）镥-177放射免疫疗法; 3）溶瘤脊髓灰质炎/鼻病毒重组体; 4）BCNU诱导的DNA链间交联修复抑制剂。 具体目标2。确定本项目临床试验中评价的治疗药物对生活质量的影响。

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.