Bispecific Antibody Therapeutics for Neuroblastoma and Diffuse Midline Glioma

项目摘要/摘要 明确识别的障碍破坏了对患有固体或其他疾病的儿童患者进行免疫治疗的前景 脑瘤。这些肿瘤中的大多数缺乏编码免疫原性蛋白的基因突变。双特异性T细胞 BTE通过将癌细胞与内源性宿主T细胞连接起来，具有克服这一障碍的潜力 细胞，绕过T细胞受体-MHC I相互作用诱导T细胞增殖和T细胞介导的癌细胞 死亡。实体肿瘤中的其他障碍在本申请中得到了解决。第一个障碍是缺乏 许多儿童实体瘤和脑瘤中的内源性T细胞。目标1寻求加强T细胞贩运到 实体或脑肿瘤通过两种互补的策略，涉及自分解聚合趋化因子。 目标1的意义在于，促进T细胞向儿童实体肿瘤渗透的解决方案将 为不可切除或转移性实体和脑肿瘤启用BTE选项，有可能将无法治愈的 癌症变得可治愈。2号屏障是脑肿瘤患者独有的，它是血脑屏障，它阻止了许多 免疫疗法进入大脑。目标2的动机是我们实验室的一个出乎意料的结果 我们设计的新型BTE正在显著提高患者来源的小鼠模型的存活率 弥漫性中线胶质瘤(DMG，又名DIPG)，尽管血脑屏障相对完整。我们试图理解 为什么这种BTE能够接触到肿瘤并延长生存时间。我们还寻求进一步优化BTE和 在各种DMG型号中测试它。目标2的意义是DMG患者的平均寿命 预期12个月，这种分子代表了一种免疫治疗选择，不需要 细胞工程学。免疫治疗的第三个障碍是大多数BTE的CD3结合成分 晚期临床开发通过高亲和力CD3结合域与T细胞上的CD3结合，1)触发 过度释放细胞因子，在一些患者中导致危及生命的细胞因子释放综合征(CRS)， 2)加速T细胞的耗竭，3)促进BTE在肝和脾的滞留。《目标3》试图发现 可诱导癌细胞的新型CD3结合蛋白(如全人抗体或单链结合蛋白) 死亡与更少的责任。这种CD3活页夹已经被其他人发现，但在行业中被锁定在 没有向儿科癌症研究人员提供访问权限。目标3的意义在于，我们的候选人可能是 被替换到儿科免疫治疗网络中的BTES增加了由此产生的分子 将更安全、更有效(因为如果CRS风险为 减少)，并更高效地开发。我们实验室发现的几种蛋白质疗法正在取得进展 临床发展。我们理应克服这些障碍中的一个或多个，以帮助社会 为患有免疫性“冷”实体瘤或脑瘤的儿童提供有效的“现成”免疫疗法。 虽然这些目标是独立的，但它们有可能相互协作，并与所取得的发现协同工作。 我们儿科免疫治疗网络的同事。

PROJECT SUMMARY/ABSTRACT Clearly identified barriers have undermined the promise of immunotherapy for pediatric patients with solid or brain tumors. Most of these tumors lack genetic mutations that encode immunogenic proteins. Bispecific T cell engagers (BTEs) have potential to overcome this barrier by connecting cancer cells to endogenous host T cells, bypassing T cell receptor-MHC I interactions to induce T cell expansion and T cell-mediated cancer cell death. Additional barriers in solid tumors are addressed in this application. Barrier #1 is the paucity of endogenous T cells in many pediatric solid and brain tumors. Aim 1 seeks to enhance T cell trafficking into solid or brain tumors via two complementary strategies that involve self-disassembling polymeric chemokines. The significance of Aim 1 is that a solution for promoting T cell infiltration into pediatric solid tumors will enable BTE options for non-resectable or metastatic solid and brain tumors, potentially converting incurable cancers to curable. Barrier #2, unique to brain tumor patients, is the blood brain barrier, which precludes many immunotherapeutics from entering the brain. Aim 2 was motivated by the unexpected result in our lab that a novel BTE that we engineered is driving significantly improved survival in a patient-derived mouse model of diffuse midline glioma (DMG, aka DIPG) despite a relatively intact blood brain barrier. We seek to understand why this BTE is able to access the tumor and extend survival. We also seek to further optimize the BTE and test it in a variety of DMG models. The significance of Aim 2 is that DMG patients have an average life expectancy of 12 months, and this molecule represents an immunotherapeutic option that does not require cellular engineering. Barrier #3 immunotherapy is that the CD3-binding components of most BTEs that have advanced to clinical development bind to CD3 on T cells via high-affinity CD3 binding domains that 1) trigger excessive cytokine release, which causes life-threatening cytokine release syndrome (CRS) in some patients, 2) accelerates T cell exhaustion, and 3) drives BTE sequestration in liver and spleen. Aim 3 seeks to discover novel CD3 binding proteins (e.g., fully human antibodies or single chain binders) that can induce cancer cell death with fewer liabilities. Such CD3 binders have been discovered by others but are locked in industry with no access provided to pediatric cancer researchers. The significance of Aim 3 is that our candidates could be substituted into Pediatric Immunotherapy Network BTEs to increase the likelihood that the resulting molecules will be safer, more effective (because higher maximally tolerated doses might be expected if CRS risk is reduced), and more efficiently developed. Several protein therapeutics discovered in our lab are advancing in clinical development. We are ideally poised to overcome one or more of these barriers to help the community provide effective “off-the-shelf” immunotherapy for children with immunologically “cold” solid or brain tumors. While independent, the Aims have potential to work synergistically with each other and with discoveries made by our colleagues in the Pediatric Immunotherapy Network.