Targeting macrophages to sensitize myeloma to immune checkpoint blockade

项目摘要 免疫检查点阻断已成为通过恢复T细胞效应物来治疗癌症的有希望的方法 功能和破坏肿瘤容许微环境。临床疗效显著，反应持久， PD-1检查点阻断的低毒性已经在各种恶性肿瘤中观察到， 血液癌症然而，在纳武单抗（抗PD-1抗体; BMS-936558）的1期研究中，没有任何一项 27例多发性骨髓瘤（MM）患者经历了部分或完全缓解，而客观 在约40%的滤泡性淋巴瘤或弥漫性大B细胞淋巴瘤患者中观察到应答。 正如我们和其他人已经表明，MM细胞表达高水平的PD-L1，骨髓（BM）浸润性T淋巴细胞（T淋巴细胞）表达高水平的PD-L1。 细胞主要是PD-1阳性，更重要的是，MM细胞携带的体细胞突变量类似于 对于B细胞淋巴瘤，对PD-1抗体治疗MM无应答不能解释为缺乏 肿瘤浸润性T细胞或PD-L1或MM细胞或免疫细胞的新抗原表达。我们推测 PD-1/PD-L1检查点阻断不足以破坏MM中的容许微环境 因为BM浸润的免疫抑制细胞，如肿瘤相关的MΦ，髓源性抑制因子， 细胞（MDSC）和/或调节性T细胞（TCFs）仍然可以抑制MM特异性效应T细胞的功能 检查站封锁后恢复。事实上，我们的初步研究表明，与人类MM相似，PD-1 mAb对小鼠模型中已建立的MM无显著治疗作用。然而，令我们惊讶的是， 在PD-1治疗后，体内MΦ的消耗，而不是MDSC或TGFAP的消耗，导致显著的抗MM作用。 检查站封锁。该应用将验证我们的假设，即MΦs作为主要的BM浸润细胞之一， 细胞类型，在抑制肿瘤微环境中的T细胞免疫中至关重要， 将显著提高MM患者中检查点阻断的治疗效果。 确定MΦs在PD-1检查点阻断治疗原发性耐药中的作用和机制， 毫米目的2将阐明MΦ介导的免疫抑制机制，目的3将确定 本发明提供了组合MΦ靶向和PD-1抗体以治疗人MM的翻译潜力。 这些目标将为临床靶向BM浸润MΦ以使MM患者敏感提供依据和工具 PD-1检查点抑制剂拟议的研究也将导致更好地了解基本的 PD-1检查点阻断的主要耐药机制，并可能为第一个 通过靶向治疗MM和其他血液恶性肿瘤， MΦs和PD-1抑制。

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.