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

项目摘要 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。的 这种疾病普遍是致命的，目前的标准治疗是无效的和使人衰弱的。癌 免疫疗法已经显示出针对多种侵袭性癌症的显著临床成功， 越来越多的证据表明，增强身体的免疫系统可以帮助消除高度侵略性， 晚期肿瘤，包括那些对常规治疗有抵抗力的肿瘤。然而，它对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未能 在患者的治疗效果上有显著的改善。我们和其他人最近发现， GBM细胞过表达先天性检查点CD 47以逃避专业抗原的检测和清除 提呈细胞（APC）。CD 47的表达水平也与GBM的生存率相关 患者然而，多项研究表明，CD 47的阻断提供了适度的生存益处， 在人类癌症的临床前模型和其他吞噬检查点如β2微球蛋白中， (B2m)已经鉴定MHC-I分子亚基促进肿瘤免疫逃避。破坏B2 M 与其吞噬细胞受体白细胞Ig样受体B1（LILRB 1）相互作用促进了 对CD 47阻断具有抗性的肿瘤细胞的多样性集合。然而，当抗CD 47和抗B2 m 单独施用抗体时，我们没有观察到GBM吞噬作用的改善。因此，我们认为， 基于这些发现，我们假设同时阻断吞噬检查点CD 47和 B2 m将激活针对GBM的先天免疫应答，从而产生有效且持久的适应性抗肿瘤药物。 免疫力为此，我们开发了一种新的双特异性抗体（CD 47-B2 m）， 脑屏障（BBB）。该提案的目标1将机械地检查CD 47-B2 m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细胞应答。在目标2中，我们 研究先天性免疫传感途径是否在桥接先天性和适应性抗肿瘤免疫中至关重要 在通过CD 47-B2 m阻断吞噬检查点的情况下。最后，在目标3中，我们将评估 CD 47-B2 m作为GBM临床相关小鼠模型中GBM的新型免疫抑制剂， 单药治疗或与放射联合治疗。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，支持进一步的研究。 一种全新抗GBM免疫抑制剂的研究此外，产生的结果 这里将强调桥接先天免疫和适应性免疫的重要性，以产生最佳的免疫应答。 抗肿瘤免疫反应。靶向多个吞噬检查点的概念可以应用于 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， 癌症免疫疗法

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.