Macrophage-based Therapy and Immune Checkpoint Blockade for Glioblastoma

胶质母细胞瘤的巨噬细胞治疗和免疫检查点阻断

• 批准号: 10602755
• 负责人: Shideng Bao
• 金额: $ 36.83万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602755
• 关键词: Alzheimer' s Disease; Biological Assay; CD34 gene; Cells; Clinical Trials; Combined Modality Therapy; Development; Dose; Engraftment; Future; Glioblastoma; Glioma; Growth; Hematopoietic stem cells; Human; Immune; Immune checkpoint inhibitor; Immunosuppression; Immunotherapy; Infiltration; Label; Low Dose Radiation; Macrophage; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Metastatic malignant neoplasm to brain; Modeling; Molecular; Molecular Target; Mus; Nature; Outcome; Patients; Phagocytosis; Primary Brain Neoplasms; Prognosis; Resistance; T-Lymphocyte; Therapeutic; Treatment Efficacy; Tumor Promotion; Tumor-associated macrophages; Xenograft procedure; beta-site APP cleaving enzyme 1; cancer therapy; checkpoint inhibition; cytokine; design; drug candidate; humanized mouse; immune checkpoint blockade; improved; induced pluripotent stem cell; inhibitor; novel therapeutic intervention; pharmacologic; preclinical study; programs; screening; small molecule; stem cells; synergism; therapeutic target; therapeutically effective; therapy resistant; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

Project Summary Glioblastoma (GBM), the most lethal primary brain tumor with poor prognosis, is highly resistant to current treatments, including immune checkpoint blockade (ICB) partially due to the immune suppressive microenvironment. GBM harbors abundant tumor-associated macrophages (TAMs) that are critical immune cells in the tumor microenvironment (TME). Because the majority of TAMs are tumor-promoting macrophages (pTAMs, M2-like) that augment malignant growth, promote therapeutic resistance, and mediate immune suppression, reprograming pTAMs into tumor-suppressive macrophages (sTAMs, M1-like) represents a promising therapeutic strategy. As pTAMs establish the immunosuppressive microenvironment that negatively impacts current immunotherapy, redirecting pTAMs into sTAMs not only activates macrophage phagocytosis of glioma cells but may also remodel the immune microenvironment to facilitate current ICB. To identify small molecules that can reprogram pTAMs into sTAMs to promote macrophage phagocytosis of glioma cells, we designed a cell-based fluorescent screening assay, using GFP-labeled iPSC-derived macrophages and tdTomato-expressing glioma cells including glioma stem cells (GSCs) to discover drug candidates and corresponding molecular targets. To this end, we found that several specific inhibitors of BACE1 (β-site amyloid precursor protein cleaving enzyme 1) could effectively stimulate macrophage phagocytosis to engulf glioma cells including GSCs, and thus identified BACE1 as a therapeutic target to reprogram pTAMs into sTAMs. We demonstrated that BACE1 is preferentially expressed by pTAMs in human GBMs and is required for maintaining pTAM polarization. Importantly, pharmacological inhibition of BACE1 by its inhibitor MK-8931 (Verubecestat) potently redirected pTAMs into sTAMs and promoted macrophage phagocytosis of glioma cells to inhibit GBM growth. Furthermore, we found that low doses of radiation (IR) markedly enhanced TAM infiltration and synergized with MK-8931 treatment to suppress GBM tumor growth. As several BACE1 inhibitors including MK-8931, initially developed for Alzheimer's disease, have been demonstrated to be safe for humans in clinical trials, repurposing these inhibitors for the macrophage-based cancer therapy should straightforward and promising. As abundant pTAMs largely contribute to the immune suppressive microenvironment, reprograming pTAMs into sTAMs through BACE1 inhibition may remodel the TME to facilitate current ICB. Thus, we hypothesize that reprograming pTAMs into sTAMs through pharmacological inhibition of BACE1 synergizes with current immune checkpoint inhibition to improve therapeutic efficacy for GBM. We will accomplish our objectives through the following aims: (1) We will assess the effect of reprograming pTAMs into sTAMs on the immune microenvironment in GBM; and (2) We evaluate the therapeutic impact of TAM-based therapy in combination with current ICB for GBM. The outcomes will inform future clinical trials to improve treatment for GBM and potentially brain metastases.

项目摘要 胶质母细胞瘤（GBM）是最致命的原发性脑肿瘤，预后差，对目前的治疗具有高度抗性。 治疗，包括免疫检查点阻断（ICB），部分原因是免疫抑制 微环境。GBM含有丰富的肿瘤相关巨噬细胞（TAM），这些巨噬细胞是关键的免疫调节因子。 肿瘤微环境（TME）因为大多数TAM是促肿瘤巨噬细胞 （pTAMs，M2样），增加恶性生长，促进治疗抗性，并介导免疫 抑制，将pTAMs重编程为肿瘤抑制性巨噬细胞（sTAMs，M1样）代表了一种 有前途的治疗策略。随着pTAMs建立免疫抑制微环境， 影响当前的免疫疗法，将pTAMs重定向为sTAMs不仅激活巨噬细胞吞噬 但也可能重塑免疫微环境以促进当前的ICB。识别小 分子可以将pTAMs重编程为sTAMs，以促进胶质瘤细胞的巨噬细胞吞噬作用，我们 设计了一种基于细胞的荧光筛选试验，使用GFP标记的iPSC衍生的巨噬细胞， 表达tdTomato的神经胶质瘤细胞，包括神经胶质瘤干细胞（GSC），以发现候选药物， 对应的分子靶点。为此，我们发现几种特异性的BACE 1（β-位点）抑制剂， 淀粉样前体蛋白裂解酶1）能有效地刺激巨噬细胞吞噬 包括GSC在内的神经胶质瘤细胞，并因此将BACE 1鉴定为将pTAM重编程为 STAM。我们证明了BACE 1优先由人GBM中的pTAMs表达，并且是必需的。 用于维持pTAM极化。重要的是，通过其抑制剂MK-8931对BACE 1的药理学抑制 （Verubecestat）有效地将pTAM重定向为sTAM，并促进胶质瘤细胞的巨噬细胞吞噬作用 以抑制GBM生长。此外，我们发现低剂量的辐射（IR）显着提高TAM 细胞浸润，并与MK-8931处理协同抑制GBM肿瘤生长。作为多个BACE 1 包括MK-8931在内的抑制剂，最初是为阿尔茨海默病开发的，已被证明是安全的 对于临床试验中的人类，将这些抑制剂重新用于基于巨噬细胞的癌症治疗， 坦率而有前途。由于丰富的pTAM在很大程度上有助于免疫抑制， 在微环境中，通过BACE 1抑制将pTAM重编程为sTAM可以重塑TME， 方便当前的ICB。因此，我们假设通过将pTAM重编程为sTAM， BACE 1的药理学抑制与当前的免疫检查点抑制协同作用， GBM的治疗效果。我们将通过以下目标实现我们的目标：（1）我们将 评估将pTAM重编程为sTAM对GBM中免疫微环境的影响;以及（2）我们 评价基于TAM的治疗与当前ICB联合治疗GBM的疗效。成果 将为未来的临床试验提供信息，以改善GBM和潜在脑转移的治疗。