Therapeutically Targeting Plasmacytoid Dendritic Cells in Multiple Myeloma

项目总结 在我们之前由美国国立卫生研究院资助的研究中，我们确定了骨髓微环境的作用 促进多发性骨髓瘤(MM)细胞的生长、存活和耐药。重要的是，我们有 成功翻译了多部小说代理商(Bortezomib、carfilzomib、来那度胺和泊马度胺) 针对从长凳到床边的这些相互作用，以及FDA对MM治疗的批准， 尽管有新的治疗方法，但在许多病例中MM仍然无法治愈，这表明有必要进一步确定 宿主-MM骨髓微环境中介导肿瘤发生和耐药性的因素。我们的研究 首次证明骨髓微环境中的浆细胞样树突状细胞(PDCs) 多发性骨髓瘤特有的免疫缺陷；以及促进肿瘤细胞的生长、存活和耐药性。 具体地说，我们发现MM患者骨髓中PDCs的数量和分布频率高于MM患者BM 正常的BM。MM BM中PDCs数量增加的功能意义从我们的 观察到PDCs：对新的和传统的治疗方法相对耐受；保护肿瘤细胞免受 治疗诱导的细胞毒性；以及促进肿瘤生长和存活。异常的PDC功能是 它们不仅与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 PDCs和/或PDCs与MM和MM BM环境中的免疫效应细胞相互作用将增强抗- 肿瘤免疫和细胞毒性。目前的建议旨在针对pDC和pDC-MM-T-NK细胞的相互作用 在以恢复抗MM免疫、增强MM细胞毒性为目标的MM的新治疗策略中， 克服耐药性，改善患者预后。我们建议使用两个不同的、但 相互关联和互补的方法：1)在MM BM环境中消耗PDC(目标1)，使用 针对功能障碍的pDC的新治疗策略；和2)pDC免疫的恢复 通过触发PDC成熟和/或阻断免疫检查点介导PDC-T细胞、PDC-NK发挥作用 细胞，以及PDC-MM细胞相互作用(目标2)。为了实现这些目标，我们将采取以下具体措施 目标：特定目标1：研究pDC耗竭作为MM的一种新疗法。(1a)进行I/II期 新药SL-401清除功能障碍的pDC的临床试验。(1B)进行临床前疗效检查 PDC耗竭的抗MM治疗。特异性目标2：通过诱导pDC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 互动。因此，目前的提议是创新的，因为它将第一次将我们的研究转化为 针对MM-PDCs进行床边和临床试验，并为未来的临床前研究提供基础 结合新的基于免疫的疗法。

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.