Targeting macrophages to sensitize myeloma to immune checkpoint blockade

靶向巨噬细胞使骨髓瘤对免疫检查点阻断敏感

• 批准号: 10091406
• 负责人: Qing Yi
• 金额: $ 33.51万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091406
• 关键词: B-Cell Lymphomas; Beds; Blood; Bone Marrow; Bone Marrow Cells; Cells; Chemoresistance; Clinical; Development; Disease; Drug resistance; Failure; Follicular Lymphoma; HLA G antigen; Hematologic Neoplasms; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunosuppression; In complete remission; Knowledge; Lead; Leukocytes; Macrophage Colony-Stimulating Factor Receptor; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Monoclonal Antibodies; Multi-Drug Resistance; Multiple Myeloma; Mus; Myeloid-derived suppressor cells; Nivolumab; PD-1/PD-L1; Patients; Plasma Cells; Play; Population; Publishing; Regulatory T-Lymphocyte; Resistance; Role; Somatic Mutation; Surface; T cell response; T-Lymphocyte; Testing; Therapeutic Effect; Toxic effect; Transcript; Treatment Efficacy; Treatment Failure; United States; anti-PD1 antibodies; anti-PD1 therapy; bone; cell type; checkpoint therapy; chemotherapy; clinical efficacy; conditioning; effective therapy; effector T cell; experience; immune checkpoint blockade; improved; in vivo; large cell Diffuse non-Hodgkin' s lymphoma; macrophage; mouse model; neoantigens; novel; novel therapeutics; partial response; patient derived xenograft model; phase 1 study; programmed cell death ligand 1; programmed cell death protein 1; relapse patients; response; tool; tumor; tumor microenvironment

Project Summary Immune checkpoint blockade has emerged as a promising approach to treat cancer by restoring T cell effector function and breaking a tumor-permissive microenvironment. Remarkable clinical efficacy, durable response, and low toxicity of PD-1 checkpoint blockade have been observed in various malignancies including hematological cancers. However, in a phase 1 study of nivolumab (anti-PD-1 antibody; BMS-936558), none of 27 patients with multiple myeloma (MM) experienced a partial or complete response, whereas objective responses were observed in about 40% of patients with follicular lymphoma or diffuse large B cell lymphoma. As we and others have shown that MM cells express high levels of PD-L1, that bone marrow (BM)-infiltrating T cells are largely PD-1 positive, and more importantly MM cells carry somatic mutations in amounts similar to as B-cell lymphomas, the absence of response to PD-1 antibody therapy for MM cannot be explained by a lack of tumor-infiltrating T cells or PD-L1 or neoantigen expression by MM cells or immune cells. We speculated that PD-1/PD-L1 checkpoint blockade alone is insufficient to break the permissive microenvironment in MM because BM-infiltrating immunosuppressive cells, such as tumor-associated MΦs, myeloid-derived suppressor cells (MDSCs), and/or regulatory T cells (Tregs) could still inhibit the function of MM-specific effector T cells restored by the checkpoint blockade. Indeed, our preliminary studies showed that, similar to human MM, PD-1 mAbs had no significant therapeutic effect against established MM in murine models. However, to our surprise, in vivo depletion of MΦs, but not MDSCs or Tregs, resulted in significant anti-MM effects following PD-1 checkpoint blockade. This application will test our hypothesis is that MΦs, as one of the major BM-infiltrating cell types, are crucial in suppressing T-cell immunity in the tumor microenvironment, and targeting these cells will significantly improve the therapeutic efficacy of checkpoint blockade in patients with MM. Aim 1 will determine the role and mechanism of MΦs in the primary resistance to PD-1 checkpoint blockade therapy in MM. Aim 2 will elucidate the mechanisms of MΦ-mediated immune suppression, and Aim 3 will determine the translational potential of combining MΦ-targeting and PD-1 antibodies to treat human MM. Accomplishing these aims will provide the justification and tools to clinically target BM-infiltrating MΦs to sensitize MM patients to PD-1 checkpoint inhibitors. The proposed studies will also lead to a better understanding of the fundamental mechanisms underlying the primary resistance to PD-1 checkpoint blockade and could pave the way to the first substantial improvements in the treatment in MM and other hematological malignancies by way of targeting MΦs and PD-1 inhibition.

项目摘要 免疫检查点封锁已成为通过恢复T细胞效应器来治疗癌症的承诺方法 功能并打破肿瘤的微环境。显着的临床效率，持久反应， 在包括 血液学癌。但是，在Nivolumab的1期研究（抗PD-1抗体； BMS-936558）中，没有 27例多发性骨髓瘤（MM）患者有部分或完全反应，而目的 在大约40％的卵泡淋巴瘤或弥漫性大B细胞淋巴瘤患者中观察到反应。 正如我们和其他人表明，MM细胞表达了高水平的PD-L1，骨髓（BM）浸润T 细胞在很大程度上是PD-1阳性的，更重要的是MM细胞的体细胞突变的量相似 B细胞淋巴瘤，无法解释对MM的PD-1抗体治疗的反应 MM细胞或免疫细胞的肿瘤浸润T细胞或PD-L1或新抗原表达。我们推测 仅PD-1/PD-L1检查点封锁不足以打破MM允许的微环境 因为BM浸润的免疫抑制细胞（例如肿瘤相关的MφS），髓样衍生的抑制剂 细胞（MDSC）和/或调节性T细胞（TREG）仍然可以抑制MM特异性效应T细胞的功能 由检查点封锁恢复。实际上，我们的初步研究表明，与人类MM相似，PD-1 在鼠模型中，mAb对建立的MM没有显着的热效应。但是，令我们惊讶的是 MφS的体内耗竭，而不是MDSC或Tregs，导致PD-1后显着抗MM效应 检查点封锁。该应用将检验我们的假设是MφS，作为主要的BM渗透之一 细胞类型对于抑制肿瘤微环境中的T细胞免疫至关重要，并针对这些细胞 在MM患者中，将显着提高检查点阻滞的治疗效率。目标1意志 确定MφS在对PD-1检查点阻滞治疗的主要抗性中的作用和机制 毫米。 AIM 2将阐明Mφ介导的免疫抑制的机制，AIM 3将确定 结合Mφ靶向和PD-1抗体以治疗人MM的转化潜力。完成 这些目的将为临床上的MM患者提供临床介入Mφ的临床介入Mφ的理由和工具 到PD-1检查点抑制剂。拟议的研究还将更好地理解基本 对PD-1检查点封锁的主要电阻的基础机制，并可以铺平到第一个的方式 通过靶向，MM和其他血液学恶性肿瘤的治疗方法进行了重大改善 MφS和PD-1抑制。