Image-guided dosimetry-based alpha particle therapy for neuroblastoma.

意义：神经母细胞瘤是最常见的儿科癌症，占癌症死亡的15%， 由于耐药转移，5年生存率<40%。神经母细胞瘤肿瘤几乎普遍表达 生长抑素受体2（SSTR 2）和高表达已经在临床上使用靶向SSTR 2的肽显示 （PMID10706954）。FDA批准的SSTR 2靶向β（β-）发射177 Lu标记的Lutathera™已显示出 安全可行（PMID 21680680），但肿瘤对SSTR 2靶向β-治疗的反应较差。上 另一方面，Viewpoint的下一代SSTR 2靶向[212 Pb]VMT-α-NET α（α）-粒子治疗（α-PRRT） 在70%的携带SSTR 2+肿瘤的小鼠中产生完全反应（CR）。数据显示， 与竞争性SSTR 2靶向放射性药物相比，VMT-α-NET的PK特性改善， 显著改善肿瘤至正常的蓄积，降低毒性风险（特别是在剂量限制性肾脏中）。在 在修改后的申请中，该团队引入了一种创新的免疫能力基因工程转移性肿瘤， 神经母细胞瘤的小鼠模型（GEMM）（全国儿童医院的新合作研究者王博士）， 在基因上模仿人类的神经母细胞瘤，并在小鼠中自发发展。因此，我们将确定有效的 方案并评估潜在的毒性（例如，肾脏）和炎症标志物，以准备FDA提交。 修订后的项目具有重要意义，因为同品种器械数据证明Viewpoint的[212 Pb]VMT-α-NET α-PRRT有可能为神经母细胞瘤提供完全/持久的肿瘤缓解（并且耐受性良好） 患者该项目具有更重要的意义，因为GEMM啮齿动物模型和CMC计划是一致的 FDA关于微剂量放射性药物治疗的指南以及我们与FDA的沟通， 快速通道指定。因此，迫切需要将Viewpoint的α-PRRT推进临床试验， 其他疗法（包括SSTR 2 β-粒子疗法）不适用的神经母细胞瘤患者。 类似里程碑：1300万美元A轮融资; 70%的小鼠CR; 203 Pb/212 Pb安全;与FDA沟通 在FDA的支持下，获得两个IND并完成IND前会议，用于成人α粒子治疗 审判FDA正在进行沟通。我们将通过完成这些具体目标来实现我们的目标。 AIM 1.确定[203 Pb]VMT-α-NET图像引导[212 Pb]VMT-α-NET治疗的给药方案， 在转移性神经母细胞瘤小鼠模型中使完全反应最大化并使毒性最小化。 AIM 2.优化[212 Pb]VMT-α-NET生产并完成CMC和IND的技术转让 向美国FDA提交申请，在神经母细胞瘤患者中启动1期成像引导治疗试验。 影响：随着这些目标的完成，我们期望对 在神经母细胞瘤转移模型中使肿瘤反应最大化（使毒性最小化）的治疗方案 符合FDA快速通道应用指南的小鼠。我们还希望完成制定工作， 提交Viewpoint达特治疗神经母细胞瘤1期试验IND的CMC文件。

SIGNIFICANCE: Neuroblastoma is the most common pediatric cancer, accounting for 15% of cancer deaths, with a 5-yr survival of <40% due to resistant metastases. Neuroblastoma tumors almost universally express the somatostatin receptor 2 (SSTR2) and high expression has been shown clinically using peptides targeting SSTR2 (PMID10706954). FDA approved SSTR2-targeted beta(β-)-emitting 177Lu-labeled Lutathera™ has been shown to be safe and feasible (PMID21680680), but tumor response to SSTR2-targeted β--therapy has been poor. On the other hand, Viewpoint’s next-generation SSTR2-targeted [212Pb]VMT-α-NET alpha(α)-particle therapy (α-PRRT) produced complete responses (CRs) in 70% of mice bearing SSTR2+ tumors. Data show that the significantly improved PK properties of VMT-α-NET compared to competing SSTR2 targeted radiopharmaceuticals leads to significantly improved tumor to normal accumulation and lower risk of toxicities (particularly in dose limiting kidneys). In the revised application, the team introduces an innovative immune-competent genetically engineered metastatic mouse model (GEMM) of neuroblastoma (new Co-Investigator Wang PhD at Nationwide Children’s Hospital) that genetically mimics neuroblastoma in humans and develops spontaneously in mice. Thus, we will identify effective regimens and assess potential toxicities (e.g., kidney) and inflammatory markers in preparation for FDA submissions. The revised project is significant because predicate data demonstrate that Viewpoint’s [212Pb]VMT-α-NET α-PRRT has the potential to provide for complete/durable tumor responses (and be well tolerated) for neuroblastoma patients. The project is further significant because the GEMM rodent model and CMC plan included is aligned with FDA guidance for micro-dosed radiopharmaceutical therapeutics and our communications with the FDA for Fast Track designation. Therefore, there is a critical need to advance Viewpoint’s α-PRRT to clinical trials for neuroblastoma patients for whom other therapies (including SSTR2 β-particle therapy) fall short. PREDICATE MILESTONES: $13M Series A; 70% CRs in mice; 203Pb/212Pb secured; Communications with FDA to secure two INDs and complete a pre-IND meeting with support from the FDA for α-particle therapy for adult trials. FDA communications are ongoing. We will achieve our objectives by completing these Specific Aims. AIM 1. Determine the dosing regimens of [203Pb]VMT-α-NET image-guided [212Pb]VMT-α-NET therapy that maximize complete responses and minimize toxicity in mouse models of metastatic neuroblastoma. AIM 2. Optimize [212Pb]VMT-α-NET production and complete technology transfer for CMC and IND submission to the US FDA to initiate a Phase 1 imaging-guided therapy trial in neuroblastoma patients. IMPACT: With completion of these Aims, we expect to have developed a detailed understanding of the therapeutic regimens that maximize tumor responses (minimizing toxicity) in metastatic models of neuroblastoma in mice that align with FDA guidance for a Fast Track application. We further expect to complete formulation and CMC documentation for the submission of an IND for Phase 1 trials of Viewpoint’s TAT for neuroblastoma.