Therapeutically Targeting Plasmacytoid Dendritic Cells in Multiple Myeloma

项目摘要 在我们先前的研究中，我们确定了骨髓（BM）微环境的作用， 在多发性骨髓瘤（MM）细胞中赋予生长、存活和耐药性。重要的是我们有 成功翻译了多种新型药物（硼替佐米、卡非佐米、来那度胺和泊马度胺） 针对这些相互作用从实验室到床边和FDA批准治疗MM。然而， 尽管有新的治疗方法，MM在许多情况下仍然无法治愈，这表明需要进一步鉴定 宿主MM BM微环境中介导肿瘤发生和耐药性的因子。我们的研究 提供了第一个证据，即骨髓微环境中的浆细胞样树突状细胞（pDC）既介导 MM中的特征性免疫缺陷;以及促进肿瘤细胞生长、存活和耐药性。 具体地，我们显示MM患者BM中pDC的数量增加，并且比MM患者BM中pDC的定位更频繁。 正常BM。MM BM中pDC数量增加的功能意义从我们的研究中是明显的。 pDC：对新的和常规的疗法具有相对的抗性;保护肿瘤细胞免于 治疗诱导细胞毒性;以及促进肿瘤生长和存活。异常pDC功能是 其不仅与MM细胞相互作用，而且与其他免疫效应T细胞和NK细胞相互作用， 从而抑制MM的免疫反应。基于这些发现，我们假设直接靶向 pDC和/或pDC与MM和MM BM环境中的免疫效应细胞的相互作用将增强抗MM和免疫效应细胞两者。 肿瘤免疫和细胞毒性。目前的提议旨在靶向pDC和pDC-MM-T-NK细胞相互作用 在MM的新治疗策略中，目的是恢复抗MM免疫力，增强MM细胞毒性， 克服耐药性，改善患者的预后。我们建议使用两个不同的，但 1）在MM BM环境中消耗pDC（目标1），使用免疫抑制剂， 特异性针对功能失调的pDC的新的治疗策略;和2）pDC免疫的恢复 通过触发pDC成熟和/或阻断介导pDC-T细胞、pDC-NK 细胞和pDC-MM细胞相互作用（目的2）。为了实现这些目标，我们将采取以下具体措施： 目的：具体目的1：研究pDC耗竭作为MM的新疗法。 新试剂SL-401消耗功能失调的pDC的临床试验。(1b)临床前检查 抗MM疗法与pDC耗竭。具体目标2：通过诱导pDC来恢复pDC的免疫功能 成熟和/或阻断介导pDC-T细胞、pDC-NK细胞或pDC-MM细胞的免疫检查点 交互.因此，目前的建议是创新的，因为它将首次将我们的研究转化为 将MM-pDC靶向于床旁和临床试验，以及为未来的研究提供临床前基础。 联合新型免疫疗法。

PROJECT SUMMARY In our prior studies supported by NIH funding we identified the role of the bone marrow (BM) microenvironment in conferring growth, survival, and drug resistance in multiple myeloma (MM) cells. Importantly, we have successfully translated multiple novels agents (bortezomib, carfilzomib, lenalidomide, and pomalidomide) targeting these interactions from the bench to the bedside and FDA approval for treatment of MM. However, MM remains incurable in many cases despite novel therapies, suggesting the need for further identification of factors in the host-MM BM microenvironment that mediate tumorigenesis and drug resistance. Our studies provided the first evidence that plasmacytoid dendritic cells (pDCs) in the BM microenvironment both mediate characteristic immune deficiency in MM; as well as promote tumor cell growth, survival, and drug resistance. Specifically, we showed increased numbers and more frequent localization of pDCs in MM patient BM than normal BM. The functional significance of increased numbers of pDCs in MM BM is evident from our observations that pDCs: are relatively resistant to novel and conventional therapies; protect tumor cells from therapy-induced cytotoxicity; as well as promote tumor growth and survival. Aberrant pDC function is evidenced in their interactions not only with MM cells, but also with other immune effector T cells and NK cells, thereby suppressing immune responses in MM. Based on these findings, we hypothesize that directly targeting pDCs and/or pDCs interactions with MM and immune effector cells in the MM BM milieu will enhance both anti- tumor immunity and cytotoxicity. The current proposal aims to target pDCs and pDC-MM-T-NK cell interactions in novel therapeutic strategies for MM with the goal of restoring anti-MM immunity, enhancing MM cytotoxicity, overcoming drug-resistance, and improving patient outcome. We propose to utilize two distinct, yet interconnected and complementary, approaches: 1) Depletion of pDCs in the MM BM milieu (Aim 1) using a novel therapeutic strategy directed specifically against dysfunctional pDCs; and 2) Restoration of pDC immune function by triggering pDC maturation and/or blocking the immune checkpoints mediating pDC-T cell, pDC-NK cell, and pDC-MM cell interactions (Aim 2). To accomplish these goals, we will pursue the following Specific Aims: Specific Aim 1: To investigate pDCs-depletion as a novel therapy in MM. (1a) To conduct a Phase I/II clinical trial of novel agent SL-401 to deplete dysfunctional pDCs. (1b) To pre-clinically examine efficacy of anti-MM therapies with pDCs depletion. Specific Aim 2: To restore pDCs immune function by inducing pDC maturation and/or blocking the immune checkpoints mediating pDC-T cell, pDC-NK cell, or pDC-MM cell interactions. The current proposal is therefore innovative, since it will for the first time translate our research targeting MM-pDCs to the bedside and clinical trials, as well as provide the pre-clinical basis for future combination novel immune-based therapies.