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

项目总结 胶质母细胞瘤(GBM)是成人最常见、最具侵袭性的原发恶性脑肿瘤。这个 疾病普遍是致命的，目前的标准治疗无效，使人虚弱。癌 免疫疗法在治疗多种侵袭性癌症和 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和 晚期肿瘤，包括那些对传统疗法耐药的肿瘤。然而，它对GBM的有效性， 目前仍不清楚，多项临床试验探索GBM的癌症免疫治疗方案失败 显示患者预后有显著改善。我们团队和其他人最近发现 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 递呈细胞(APC)。CD47的表达水平也与GBM的存活率有关 病人。然而，多项研究表明，阻断CD47提供了适度的生存益处 在人类癌症的临床前模型和额外的吞噬检查点，如β2微球蛋白 已发现MHC-I分子的(B2M)亚单位可促进肿瘤免疫逃逸。B2M的颠覆 与其吞噬细胞受体白细胞Ig样受体B1(LILRB1)相互作用促进A细胞吞噬 对CD47阻断有抵抗力的肿瘤细胞的多样性收集。然而，当抗CD47和抗B2M 抗体单独给药，我们没有观察到GBM吞噬功能的改善。因此， 基于这些发现，我们假设吞噬检查点CD47和CD47的同时阻断 B2M将激活针对GBM的先天免疫反应，导致有效和持久的适应性抗肿瘤 豁免权。为此，我们开发了一种新的双特异性抗体(CD47-B2M)，它可以很容易地跨越血液 脑屏障(BBB)。该提案的目标1将机械地检查CD47-B2M是否可以促进 APC通过诱导GBM细胞吞噬应答抗原特异性抗肿瘤T细胞在目标2中，我们将 研究先天免疫感知通路是否在先天免疫和获得性抗肿瘤免疫之间起关键作用 CD47-B2M在吞噬关卡阻断吞噬功能。最后，在目标3中，我们将评估 CD47-B2M作为一种新的免疫疗法治疗临床相关的小鼠GBM作为一种 单一治疗或联合放射治疗。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 一种全新的抗GBM免疫治疗剂的研究。此外，生成的结果 这里将强调连接先天免疫和获得性免疫的重要性，以产生最理想的 抗肿瘤免疫反应。以多个吞噬检查点为目标的概念可以应用于 有可能是所有人类癌症，如果成功，可能会提供一种新的战略，以增强治疗的有效性 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.