Bispecific Antibody Therapeutics for Neuroblastoma and Diffuse Midline Glioma

项目概要/摘要 明确确定的障碍破坏了免疫治疗儿童患者的承诺， 脑瘤这些肿瘤中的大多数缺乏编码免疫原性蛋白质的基因突变。双特异性T细胞 BTEs有可能通过将癌细胞与内源性宿主T细胞连接来克服这一障碍。 细胞，绕过T细胞受体-MHC I相互作用以诱导T细胞扩增和T细胞介导的癌细胞 死亡在本申请中解决了实体瘤中的其他屏障。障碍#1是缺乏 内源性T细胞在许多儿科实体瘤和脑肿瘤中的作用。目的1旨在增强T细胞向 实体瘤或脑肿瘤通过两种互补的策略，涉及自分解聚合物趋化因子。 目的1的意义在于，促进T细胞浸润到儿科实体瘤中的解决方案将 为不可切除或转移性实体瘤和脑肿瘤提供BTE选择， 癌症可以治愈。屏障#2是脑肿瘤患者特有的，是血脑屏障，它阻止了许多脑肿瘤患者。 免疫治疗药物进入大脑目标2的动机是我们实验室的意外结果， 我们设计的一种新型BTE正在显著改善患者来源的小鼠模型的生存率， 弥漫性中线胶质瘤（DMG，又名DIPG），尽管血脑屏障相对完整。我们寻求理解 为什么BTE能够进入肿瘤并延长生存期。我们还寻求进一步优化BTE， 在各种DMG模型中进行测试。目标2的意义在于DMG患者的平均寿命 预期12个月，这种分子代表了一种免疫选择， 细胞工程学屏障#3免疫疗法是大多数BTE的CD 3结合成分， 进入临床开发阶段的CD 3通过高亲和力CD 3结合结构域与T细胞上的CD 3结合， 过度的细胞因子释放，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细胞耗竭，和3）驱动肝脏和脾脏中的BTE隔离。目标3旨在发现 新的CD 3结合蛋白（例如，完全人抗体或单链结合剂），其可以诱导癌细胞 死亡与更少的责任。这样的CD 3结合剂已经被其他人发现，但在工业上被锁定， 不向儿科癌症研究人员提供访问权限。目标3的重要性在于，我们的候选人可以 替代到儿科免疫治疗网络BTE中，以增加产生的分子 将更安全，更有效（因为如果CRS风险是 减少），并更有效地开发。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。我们已准备好克服一个或多个障碍，以帮助社区 为患有免疫学上的“冷”实体瘤或脑肿瘤的儿童提供有效的“现成”免疫疗法。 虽然是独立的，但这些目标有可能相互协同工作，并与已取得的发现协同工作。 儿科免疫治疗网络的同事们。

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.