Therapeutic targeting of multiple glioblastoma phagocytosis checkpoints using a novel bispecific antibody

使用新型双特异性抗体靶向治疗多个胶质母细胞瘤吞噬检查点

基本信息

批准号：
10609925
负责人：
Wen Jiang
金额：
$ 43.51万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609925
关键词：
Adult Affect Anti-CD47 Antibodies Antigen-Presenting Cells Antigens Antitumor Response Binding Bispecific Antibodies Bone Marrow Brain Brain Neoplasms CD47 gene Cell Separation Cell surface Cells Clinical Clinical Research Clinical Trials Collection Colorectal Cancer Colorectal Neoplasms Combined Modality Therapy Critical Pathways Cross-Priming Cyclic GMP Cytosol Cytotoxic T-Lymphocytes DNA Sequence Alteration Data Detection Development Disease Eating Effectiveness Ensure Feedback Glioblastoma Glioma Goals Human Hybrids Immune Immune Evasion Immune response Immune system Immunotherapeutic agent In Vitro Individual Inflammatory Innate Immune Response Interferon Type I Investigation Kinetics Knock-out Lead Leukocytes Ligands Macrophage Major Histocompatibility Complex Malignant Neoplasms Malignant neoplasm of brain Mammary Neoplasms Mediating Microglia Molecular Mus Natural Immunity Pathway interactions Patient-Focused Outcomes Patients Pattern Phagocytes Phagocytosis Phagosomes Play Pre-Clinical Model Prediction of Response to Therapy Probability Process Production Radiation Receptor Signaling Regimen Research Resistance Role Signal Transduction Stimulator of Interferon Genes T cell response T-Lymphocyte Therapeutic Therapeutic Effect Therapeutic antibodies Time Toll-like receptors Tumor Escape Tumor Immunity Tumor Promotion adaptive immunity anti-tumor immune response antigen-specific T cells beta-2 Microglobulin blood-brain barrier crossing blood-brain tumor barrier cancer immunotherapy cell killing clinically relevant conventional therapy efficacy evaluation human model immune checkpoint immune checkpoint blockade improved in vivo innate immune checkpoint innate immune sensing knockout animal malignant breast neoplasm mouse model neoplastic cell novel novel therapeutic intervention overexpression patient derived xenograft model pre-clinical receptor reconstitution response spatiotemporal standard care success therapeutic target treatment response treatment strategy tumor tumor DNA tumor growth

项目摘要

PROJECT SUMMARY Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. The disease is universally fatal with current standard treatment being ineffective and debilitating. Cancer immunotherapy has demonstrated remarkable clinical success against multiple aggressive cancers and growing evidence suggests that boosting the body’s immune system can help eliminate highly aggressive and advanced tumors, including those resistant to conventional therapies. Its effectiveness against GBM, however, remains unclear, with multiple clinical trials exploring cancer immunotherapy regimens for GBM failed to demonstrate significant improvement in patient outcomes. Our group and others have recently discovered that GBM cells overexpress innate checkpoint CD47 to evade detection and clearance by professional antigen presenting cells (APCs). The expression level of CD47 was also found to correlate with survival in GBM patients. However, multiple studies showed that blockade of CD47 provided modest survival benefit in preclinical models of human cancers and additional phagocytosis checkpoints such as the β2 microglobulin (B2m) subunit of MHC-I molecule have been identified to promote tumor immune evasion. Disruption of B2m interaction with its phagocyte receptor leukocyte Ig-like receptor B1 (LILRB1) promotes phagocytosis of a diverse collection of tumor cells that were resistant to CD47 blockade. Yet, when anti-CD47 and anti-B2m antibodies were administered independently, we did not observe improved GBM phagocytosis. Therefore, based on these findings, we hypothesize that simultaneous blockade of phagocytosis checkpoints CD47 and B2m will activate innate immune responses against GBM, leading to a potent and durable adaptive antitumor immunity. To this end, we developed a novel bispecific antibody (CD47-B2m) that readily crosses the blood brain barrier (BBB). Aim 1 of the proposal will mechanistically examine whether CD47-B2m can promote antigen-specific antitumor T cell responses by APCs through induced GBM cell phagocytosis. In Aim 2, we will investigate if innate immune sensing pathways are critical in bridging innate and adaptive antitumor immunity in the setting of phagocytosis checkpoint blockade by CD47-B2m. Finally, in Aim 3, we will evaluate the use of CD47-B2m as a novel immunotherapeutic for GBM in clinically relevant murine models of GBM as a monotherapy or in combination with radiation. We will also investigate potential molecular mechanisms that predict treatment responses. If successful, our study will provide important preclinical data supporting further investigation of a completely novel immunotherapeutic agent against GBM. Additionally, the results generated here will highlight the importance of bridging innate and adaptive immunity to produce the most optimal antitumor immune responses. The concept of targeting multiple phagocytosis checkpoints can be applied to potentially all human cancers, and if successful may provide a new strategy to enhance the effectiveness of cancer immunotherapies.

项目摘要胶质母细胞瘤（GBM）是成年人中最常见和侵略性的原发性恶性脑肿瘤。这疾病普遍致命，目前的标准治疗无效且使人衰弱。癌症免疫疗法对多种侵略性癌症和越来越多的证据表明，增强人体的免疫系统可以帮助消除高度侵略性和晚期肿瘤，包括那些对常规疗法的耐药性。但是，它对GBM的有效性尚不清楚，通过多次探索GBM癌症免疫疗法方案的临床试验未能表现出患者预后的显着改善。我们的小组和其他人最近发现 GBM细胞过表达先天检查点CD47以逃避专业抗原的检测和清除呈现细胞（APC）。还发现CD47的表达水平与GBM中的存活率相关患者。但是，多项研究表明，CD47的封锁提供了适中的生存优势在人类癌症的临床前模型和其他吞噬作用检查点，例如β2微球蛋白（B2M）已鉴定出MHC-I分子的亚基来促进肿瘤免疫进化。 B2M的破坏与其吞噬细胞受体白细胞Ig样受体B1（LILRB1）的相互作用促进了A的吞噬作用抗CD47封锁具有抗性的肿瘤细胞的多种收集。但是，当抗CD47和抗B2M 抗体是独立给药的，我们没有观察到改善的GBM吞噬作用。所以，基于这些发现，我们假设对吞噬作用检查点CD47和 B2M将激活针对GBM的先天免疫调查，从而导致潜在耐用的自适应抗肿瘤免疫。为此，我们开发了一种新型的双特异性抗体（CD47-B2M），该抗体很容易跨过血液脑屏障（BBB）。该提案的目标1将机械检查CD47-B2M是否可以促进 APC通过诱导的GBM细胞吞噬作用的抗原特异性抗肿瘤T细胞反应。在AIM 2中，我们将研究先天免疫传感途径对于桥接先天和适应性抗肿瘤免疫是否至关重要在CD47-B2M的吞噬作用检查点阻断中。最后，在AIM 3中，我们将评估使用 CD47-B2M作为GBM临床相关的鼠模型GBM的新型免疫治疗性作为一种单一疗法或与辐射结合。我们还将研究潜在的分子机制预测治疗反应。如果成功，我们的研究将提供重要的临床前数据支持针对GBM的一种完全新颖的免疫治疗剂的研究。此外，结果生成这将强调桥接先天和适应性免疫以产生最佳的重要性抗肿瘤免疫反应。靶向多个吞噬作用检查点的概念可以应用于潜在的所有人类癌症，如果成功的话，可以提供一种新的策略来提高癌症免疫疗法。