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：
10212046
负责人：
Wen Jiang
金额：
$ 44.46万
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/10212046
关键词：
Adult Affect Anti-CD47 Antibodies Antigen-Presenting Cells Antigens Antitumor Response Binding Bispecific Antibodies Blood - brain barrier anatomy Bone Marrow Brain Brain Neoplasms CD47 gene 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 Interferons Investigation Kinetics Knock-out Lead Leukocytes Ligands 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 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 adaptive immunity anti-tumor immune response antigen-specific T cells base beta-2 Microglobulin blood-brain tumor barrier cancer immunotherapy cell killing clinically relevant conventional therapy human model immune checkpoint immune checkpoint blockade improved in vivo innate immune checkpoint innate immune sensing knockout animal macrophage 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.

项目概要胶质母细胞瘤（GBM）是成人中最常见和最具侵袭性的原发性恶性脑肿瘤。这种疾病普遍是致命的，目前的标准治疗方法无效且使人衰弱。免疫疗法在对抗多种侵袭性癌症方面已取得显着的临床成功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攻击性和然而，晚期肿瘤，包括那些对传统疗法有抵抗力的肿瘤，其对 GBM 的有效性。目前尚不清楚，多项探索 GBM 癌症免疫治疗方案的临床试验均未能成功我们的团队和其他人最近发现，患者的治疗结果得到了显着改善。 GBM 细胞过度表达先天检查点 CD47，以逃避专业抗原的检测和清除还发现 CD47 的表达水平与 GBM 的存活相关。然而，多项研究表明，阻断 CD47 可提供一定程度的生存获益。在人类癌症和其他吞噬检查点（例如 β2 微球蛋白）的临床前模型中 MHC-I 分子的 (B2m) 亚基已被鉴定可促进 B2m 的肿瘤免疫逃避。与其吞噬细胞受体白细胞 Ig 样受体 B1 (LILRB1) 相互作用，促进吞噬细胞然而，当抗 CD47 和抗 B2m 时，肿瘤细胞对 CD47 阻断具有抵抗力。单独施用抗体，我们没有观察到 GBM 吞噬作用的改善。基于这些发现，我们寻求同时阻断吞噬检查点 CD47 和 B2m 将激活针对 GBM 的先天免疫反应，从而产生有效且持久的适应性抗肿瘤为此，我们开发了一种新型双特异性抗体（CD47-B2m），可以轻松穿过血液。该提案的目标1将机械地检查CD47-B2m是否可以促进脑屏障。 APC 通过诱导 GBM 细胞吞噬作用产生抗原特异性抗肿瘤 T 细胞反应。研究先天免疫传感途径对于桥接先天免疫和适应性抗肿瘤免疫是否至关重要最后，在目标 3 中，我们将评估 CD47-B2m 吞噬检查点阻断的使用。 CD47-B2m 作为 GBM 临床相关小鼠模型中的一种新型免疫疗法我们还将研究单一疗法或与放射疗法相结合的潜在分子机制。如果成功，我们的研究将提供重要的临床前数据支持进一步。针对 GBM 的全新免疫治疗剂的研究此外，还产生了结果。这里将强调桥接先天免疫和适应性免疫以产生最佳效果的重要性靶向多个吞噬检查点的概念可应用于抗肿瘤免疫反应。可能是所有人类癌症，如果成功的话可能会提供一种新的策略来增强癌症的有效性癌症免疫疗法。