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.

项目概要/摘要 明确识别的障碍破坏了免疫疗法对患有实体或免疫缺陷的儿科患者的希望。 脑肿瘤。大多数这些肿瘤缺乏编码免疫原性蛋白质的基因突变。双特异性T细胞 接合者 (BTE) 有潜力通过将癌细胞与内源性宿主 T 连接来克服这一障碍 细胞，绕过 T 细胞受体-MHC I 相互作用，诱导 T 细胞扩增和 T 细胞介导的癌细胞 死亡。本申请解决了实体瘤中的其他障碍。障碍#1是缺乏 许多儿童实体瘤和脑肿瘤中存在内源性 T 细胞。目标 1 寻求增强 T 细胞运输至 通过两种涉及自拆卸聚合趋化因子的互补策略来治疗实体瘤或脑肿瘤。 目标 1 的意义在于，一种促进 T 细胞浸润儿童实体瘤的解决方案将 为不可切除或转移性实体瘤和脑肿瘤提供 BTE 选项，有可能转化为不可治愈的疾病 癌症可以治愈。脑肿瘤患者特有的第二道屏障是血脑屏障，它排除了许多 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 我们设计的新型 BTE 显着提高了源自患者的小鼠模型的生存率 尽管血脑屏障相对完整，但弥漫性中线胶质瘤（DMG，又名 DIPG）。我们寻求理解 为什么这种 BTE 能够进入肿瘤并延长生存期。我们还寻求进一步优化 BTE 和 在各种 DMG 模型中对其进行测试。目标 2 的意义在于 DMG 患者的平均寿命 预期寿命为 12 个月，该分子代表了一种免疫治疗选择，不需要 细胞工程。屏障 #3 免疫疗法是大多数 BTE 的 CD3 结合成分 进入临床开发阶段，通过高亲和力 CD3 结合域与 T 细胞上的 CD3 结合，1) 触发 细胞因子过度释放，导致某些患者危及生命的细胞因子释放综合征（CRS）， 2) 加速 T 细胞耗竭，3) 驱动 BTE 隔离在肝脏和脾脏中。目标 3 寻求发现 可诱导癌细胞的新型 CD3 结合蛋白（例如全人抗体或单链结合物） 死亡时负债较少。此类 CD3 结合剂已被其他人发现，但仍被锁定在工业界 不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以 替代儿童免疫治疗网络 BTE，以增加产生的分子的可能性 会更安全、更有效（因为如果 CRS 风险降低，则可能需要更高的最大耐受剂量） 减少），并且更有效地开发。我们实验室发现的几种蛋白质疗法正在取得进展 临床开发。我们完全有能力克服其中一个或多个障碍来帮助社区 为患有免疫学“冷”实体瘤或脑肿瘤的儿童提供有效的“现成”免疫疗法。 虽然独立，但目标有潜力相互协同工作并取得发现 由我们儿科免疫治疗网络的同事提供。