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：
9634041
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
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/9634041
关键词：
B-Cell Lymphomas Beds Blood Bone Marrow Bone Marrow Cells Cells 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 Xenograft procedure 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&apos s lymphoma macrophage mouse model neoantigens novel novel therapeutics partial response phase 1 study programmed cell death ligand 1 programmed cell death protein 1 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.

项目概要免疫检查点阻断已成为通过恢复 T 细胞效应器来治疗癌症的一种有前途的方法功能并打破肿瘤允许的微环境，显着的临床疗效，持久的反应，已在多种恶性肿瘤中观察到 PD-1 检查点阻断的低毒性，包括然而，在 nivolumab（抗 PD-1 抗体；BMS-936558）的 1 期研究中，没有发现 27 名多发性骨髓瘤 (MM) 患者出现部分或完全缓解，而客观缓解约 40% 的滤泡性淋巴瘤或弥漫性大 B 细胞淋巴瘤患者观察到缓解。正如我们和其他人已经证明 MM 细胞表达高水平的 PD-L1，骨髓 (BM) 浸润性 T 细胞大部分为 PD-1 阳性，更重要的是，MM 细胞携带的体细胞突变数量与 B 细胞淋巴瘤、多发性骨髓瘤 (MM) 对 PD-1 抗体治疗没有反应不能用缺乏我们推测，肿瘤浸润 T 细胞或 PD-L1 或新抗原由 MM 细胞或免疫细胞表达。单独阻断 PD-1/PD-L1 检查点不足以打破 MM 中允许的微环境因为骨髓浸润的免疫抑制细胞，例如肿瘤相关的 MΦ、骨髓源性抑制细胞细胞 (MDSC) 和/或调节性 T 细胞 (Treg) 仍然可以抑制 MM 特异性效应 T 细胞的功能事实上，我们的初步研究表明，与人类 MM 类似，PD-1。 mAb 对小鼠模型中已建立的 MM 没有显着的治疗效果，但令我们惊讶的是， PD-1 后，体内 MΦ 的消耗（而非 MDSC 或 Tregs 的消耗）导致了显着的抗 MM 作用该应用程序将检验我们的假设，即 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 细胞免疫以及靶向这些细胞至关重要将显着提高 MM 患者检查点阻断的治疗效果。确定 MΦs 在 PD-1 检查点阻断治疗的原发性耐药中的作用和机制 MM。目标 2 将阐明 MΦ 介导的免疫抑制机制，目标 3 将确定结合 MΦ 靶向和 PD-1 抗体治疗人类 MM 的转化潜力。这些目标将为临床靶向 BM 浸润性 MΦ 以使 MM 患者敏感提供依据和工具拟议的研究也将有助于更好地了解 PD-1 检查点抑制剂的基本原理。 PD-1 检查点封锁的主要抵抗机制，可能为第一个抵抗铺平道路通过靶向治疗显着改善多发性骨髓瘤和其他血液恶性肿瘤的治疗 MΦs 和 PD-1 抑制。