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

基本信息

批准号：
9283894
负责人：
Qing Yi
金额：
$ 32.89万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9283894
关键词：
Antibodies Antibody Therapy B-Cell Lymphomas B-Lymphocytes Beds Blood Bone Marrow Bone Marrow Cells Cells Clinical Development Diffuse Drug resistance Effector Cell Failure Follicular Lymphoma HLA G antigen Hematologic Neoplasms Human Immune Immune checkpoint inhibitor Immune response Immunity Immunosuppression Immunosuppressive Agents In complete remission Knowledge Lead Leukocytes Macrophage Colony-Stimulating Factor Receptor Malignant - descriptor Malignant Neoplasms Mediating Modeling Multiple Myeloma Mus Myelogenous PDCD1LG1 gene Patients Plasma Cells Play Population Regulatory T-Lymphocyte Resistance Role Somatic Mutation Suppressor-Effector T-Lymphocytes Surface T cell response T-Lymphocyte Testing Therapeutic Effect Toxic effect Transcript Treatment Efficacy Treatment Failure Xenograft procedure bone cell type chemotherapy clinical efficacy conditioning effective therapy experience immune checkpoint blockade improved in vivo large cell Diffuse non-Hodgkin&apos s lymphoma macrophage mouse model novel novel therapeutics partial response permissiveness phase 1 study relapse patients response tool tumor tumor microenvironment

项目摘要

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。