Bispecific Antibody Therapeutics for Neuroblastoma and Diffuse Midline Glioma

用于神经母细胞瘤和弥漫性中线胶质瘤的双特异性抗体治疗

• 批准号: 10714915
• 负责人: Vandana Kalia
• 金额: $ 86万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714915
• 关键词: Acceleration; Address; Affinity; Alpaca; Antibodies; Autologous; Automobile Driving; Binding; Binding Proteins; Biodistribution; Bispecific Antibodies; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Bypass; CD3 Antigens; Cell Death; Child; Childhood; Childhood Solid Neoplasm; Communities; Complement; Core-Binding Factor; Cystine; DNA Sequence Alteration; Data; Diffuse intrinsic pontine glioma; Engineering; Exclusion; Granzyme; Hematologic Neoplasms; Human; Immunologics; Immunologist; Immunotherapeutic agent; Immunotherapy; Industry; Injections; Life; Life Expectancy; Liver; Longevity; MLL gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Modeling; Monoclonal Antibody HuM291; Mus; Mutation; Neuroblastoma; Operative Surgical Procedures; Patients; Pediatric Hematology; Polymers; Population; Production; Protein Engineering; Proteins; Research Personnel; Risk; Safety; Solid Neoplasm; Spleen; T cell infiltration; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic antibodies; Time; Toxic effect; Treatment Failure; Tumor Antigens; Unresectable; Work; Xenograft procedure; antigen binding; bi-specific T cell engager; cancer cell; carcinogenesis; cellular engineering; chemokine; chemoradiation; clinical development; cross reactivity; cytokine; cytokine release syndrome; diffuse midline glioma; drug development; exhaustion; immunogenic; immunological synapse; implantation; improved; in vitro activity; in vivo; invention; manufacture; mouse model; neoplastic cell; new technology; next generation; novel; patient derived xenograft model; pediatric patients; perforin; preclinical development; prevent; programmed cell death ligand 1; resistance mechanism; response; therapeutic protein; trafficking; tumor; tumor microenvironment; vaccination strategy

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.

项目摘要/摘要 清楚鉴定的障碍破坏了针对固体或固体或 脑肿瘤。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 通过将癌细胞与内源宿主连接到内源性宿主T 细胞，绕过T细胞接收器MHC I相互作用以诱导T细胞扩张和T细胞介导的癌细胞 死亡。在本应用中解决了实体瘤的其他障碍。障碍1是 许多小儿固体和脑肿瘤中的内源性T细胞。 AIM 1试图增强T细胞贩运 固体或脑肿瘤通过两种完整的策略，涉及自由分配聚合物趋化因子。 目标1的意义在于，促进T细胞浸润到小儿实体瘤的解决方案将 启用BTE选项，用于不可切除或转移性固体和脑肿瘤，有可能转化无法治疗 癌症可治愈。脑瘤患者独有的障碍2是血脑屏障，这排除了许多 免疫治疗药进入大脑。 AIM 2是由我们实验室意外结果的动机 我们设计的新型BTE正在驾驶在患者衍生的小鼠模型中显着提高生存率 弥漫性中线神经胶质瘤（DMG，aka Dipg）努力相对完整的血脑屏障。我们试图理解 为什么这种BTE能够进入肿瘤并延长生存率。我们还寻求进一步优化BTE和 在多种DMG模型中对其进行测试。 AIM 2的意义是DMG患者的平均寿命 预期为12个月，该分子代表不需要的免疫治疗选择 蜂窝工程。障碍3免疫疗法是大多数BTE的CD3结合成分 通过高亲和力CD3结合结构域与T细胞上的CD3结合到临床发育。1）触发 过度细胞因子释放，导致某些患者威胁生命的细胞因子释放综合征（CRS）， 2）加速T细胞耗尽，3）在肝脏和脾脏中驱动BTE隔离。 AIM 3试图发现 可以诱导癌细胞的新型CD3结合蛋白（例如，完全人类抗体或单链粘合剂） 死亡人数较少。这种CD3粘合剂已被其他人发现，但已锁定在行业中 儿科癌症研究人员没有提供通道。目标3的意义是我们的候选人可能是 取代儿科免疫疗法网络BTE，以增加产生的分子的可能性 安全，更有效（因为CRS风险是 减少），并更有效地发展。在我们的实验室中发现的几种蛋白质疗法正在进步 临床发展。理想情况下，我们被毒死了，可以克服其中一个或多个障碍来帮助社区 为具有免疫性“冷”固体或脑肿瘤的儿童提供有效的“现成”免疫疗法。 虽然独立，但目标有可能与彼此协同合作并发现发现 由我们的小儿免疫疗法网络中的同事。