Gene-Engineered and Targeted Stem Cell Therapy for Myeloma

描述(由申请人提供)：目前多发性骨髓瘤(MM)的治疗进展导致了很高的缓解率；然而，所有患者最终都会复发并死于这种疾病。骨髓微环境中的细胞作为骨髓瘤生长和肿瘤表现的调节者与疾病过程密切相关。MM细胞通过触发核因子受体激活物-B配体(RANKL)的协同增加和骨髓中骨保护素(OPG)的减少来促进骨吸收。此外，破骨细胞主要通过破骨细胞的骨桥蛋白和MM细胞的血管内皮生长因子(VEGF)的协同作用来促进MM细胞的血管生成。血管生成效应进一步促进了骨破坏和多发性骨髓细胞扩张之间的恶性循环。因此，开发新的靶向治疗方法以消除溶骨性骨破坏、MM细胞生长以及与肿瘤血管生成相关的病理变化等关键事件，将有助于更好地管理疾病并提高患者存活率。这项建议的总体目标是开发一种新的骨髓瘤治疗模式，通过针对这些事件的靶向治疗来控制骨病、肿瘤血管生成和肿瘤细胞，将有助于控制骨髓瘤的进展。我们最近开发了一种新的方法用于基因转导的MSC的骨丰富归巢，并证明了这种经修饰表达OPG的MSC在预防溶骨性骨损伤方面的潜力。此外，通过使用编码内皮抑素和血管抑素的重组腺相关病毒载体(RAAV)，我们证明了显著延迟了肿瘤的生长和提高了长期存活率。在拟议的研究中，我们将在MM小鼠模型中确定这些治疗方法与化疗的逐步结合的效果，该模型非常接近于人类疾病的病理。拟议研究的结果将引领我们进入下一个阶段，在这一阶段，我们将设计旨在改善骨髓瘤相关骨疾病的治疗方案，并测试在预防骨髓瘤复发和人类患者疾病进展方面的治疗效果。公共卫生相关性：多发性骨髓瘤是一种B细胞恶性肿瘤，其特征是骨髓中浆细胞的渗透和生长。多发性骨髓瘤患者在颅骨、肋骨、椎骨、骨盆和四肢的长骨中发生永久性的溶骨性疾病，以骨痛、病理性骨折和高钙血症为特征，使其成为发病率的主要原因。尽管用于治疗多发性骨髓瘤患者的化疗方案取得了进展，但确诊后的中位生存期约为三年。因此，需要开发针对骨髓瘤细胞生长和增殖的多种事件的新疗法，包括骨微环境和肿瘤血管，以提高患者的存活率。这项工作的中心假设是骨靶向、基因工程MSC治疗，能够通过稳定表达OPG来抑制破骨细胞活性，将是减少MM溶骨性骨损害的有效治疗方法。通过将OPG治疗与肿瘤靶向化疗和肿瘤血管靶向抗血管生成基因治疗相结合，我们试图在临床前小鼠模型中建立一种新的治疗MM的范式。这些研究的成功完成将使我们能够启动第一阶段的人类临床试验。

DESCRIPTION (provided by applicant): Current advances in the treatment of multiple myeloma (MM) have resulted in a high rate of remissions; however, all patients eventually relapse and succumb to the disease. Cells in the bone marrow microenvironment are intimately involved in the disease process as regulators of myeloma growth and tumor manifestations. MM cells enhance bone resorption by triggering a coordinated increase in the receptor activator of nuclear factor-: B ligand (RANKL) and a decrease in osteoprotegerin (OPG) in the bone marrow. Further, osteoclasts enhance angiogenesis in concert with MM cells largely through the cooperative actions of osteopontin from osteoclasts and vascular endothelial growth factor (VEGF) from MM cells. The angiogenic effect further facilitates the vicious cycle between bone destruction and MM cell expansion. Thus, development of new, targeted therapies to abrogate key events of osteolytic bone destruction, MM cell growth and associated pathology of tumor angiogenesis, will lead to better management of the disease and increase patient survival. The overall goal of this proposal is to develop a new paradigm of myeloma therapy, whereby control of bone disease, tumor angiogenesis and tumor cells by targeted therapies to these events will help to control myeloma progression. We recently developed a novel method for bone enriched homing of genetically transduced MSC and demonstrated the potential of such MSC, modified to express OPG, in preventing osteolytic bone damage. Further, by using a recombinant adeno-associated virus vector (rAAV) encoding endostatin and angiostatin, we demonstrated significant delay in tumor growth and increase in long-term survival. In the proposed studies, we will determine the effects of these therapies in step-wise combination with chemotherapy in a mouse model of MM, which closely mimics the human disease pathology. The results of the proposed study will lead us to the next stage in which we will design treatment protocols aimed at improving myeloma-related bone disease and test treatment efficacy in preventing myeloma relapses and disease progression in human patients. PUBLIC HEALTH RELEVANCE: Multiple myeloma is a B-cell malignancy characterized by the infiltration and growth of plasma cells in the bone marrow. Patients with MM develop osteolytic bone disease permanently in the skull, ribs, vertebrae, pelvis, and long bones of the limb, characterized by bone pain, pathologic fractures, and hypercalcemia, making this a major cause of morbidity. Despite advances in chemotherapy regimens used to treat patients with MM, the median length of survival after diagnosis of the disease is approximately three years. Thus, newer therapies targeting multiple events of myeloma cell growth and proliferation, including bone microenvironment and tumor vasculature need to be developed for increasing patient survival. The central hypothesis of the proposed work is bone-targeted, genetically engineered MSC therapy capable of inhibiting osteoclast activity by stable expression of OPG will be an effective treatment for decreasing osteolytic bone lesions in MM. By combining the OPG therapy with tumor-targeted chemotherapy and tumor vasculature-targeted anti-angiogenic gene therapy we seek to establish a novel treatment paradigm for MM in a preclinical mouse model. Successful completion of these studies will allow us to initiate phase-1 human clinical trials.