Targeting DKK1 with a DNA Vaccine to Prevent Development of Multiple Myeloma

多发性骨髓瘤（MM）仍然是一种无法治愈的浆细胞癌，尽管化疗和免疫治疗取得了很大进展。所有MM患者之前都有无症状阶段，主要包括意义不确定的单克隆γ病（MGUS），通常随后发展为更严重的阴燃MM （SMM）。MGUS患者，特别是SMM患者，会转化为显性MM，并且没有治疗方法可以阻止其进展为MM。因此，开发针对MGUS和SMM的化疗和/或免疫预防策略是一个未满足的需求。Dickkopf-1 （DKK1）可能是一个很好的靶标。DKK1在包括正常骨髓（BM）浆细胞在内的正常组织中不存在，但在MGUS和SMM患者的BM浆细胞中高表达，并且在MM细胞中的表达进一步升高。我们的研究表明，DKK1是一种优秀的肿瘤相关抗原（TAA）， DKK1疫苗在体内对已建立的MM具有治疗作用。该项目的目的是首次确定以DKK1为靶点的疫苗免疫预防MM发展的潜力。这项工作将支持临床开发新的基于免疫的、毒性更小（比化疗）的MGUS或SMM患者治疗方法，以防止进展为显性MM。完成这些研究具有高度意义和临床影响，因为dkk1特异性人源化单克隆抗体已经可用，并已在人类癌症中进行了测试。

Multiple myeloma (MM) remains an incurable plasma cell cancer despite great advancements in chemo- and immunotherapies. All MM patients have preceding asymptomatic stages which primarily consist of monoclonal gammopathy of undetermined significance (MGUS), which is often followed by development of a more severe condition called smoldering MM (SMM). Patients with MGUS, and especially SMM, convert to overt MM and no therapeutic methods are available to prevent their progression to MM. Therefore, this is an unmet need to develop chemo- and/or immunoprevention strategies for MGUS and SMM. Dickkopf-1 (DKK1) may be an excellent target for this purpose. DKK1 is absent from normal tissues including normal bone marrow (BM) plasma cells but is highly expressed in BM plasma cells from MGUS and SMM patients, and their expression is further elevated in MM cells. Our studies showed that DKK1 was an excellent tumor-associated antigen (TAA), and DKK1 vaccine was therapeutic against established MM in vivo. The objective of this project is to, for the first time, determine the potential of targeting DKK1 by a vaccine for immunoprevention of MM development. This work will support the clinical development of novel immune-based, less toxic (than chemotherapy) treatments for patients with MGUS or SMM to prevent progression to overt MM. Completing these studies are highly significantly and clinically impactful, as DKK1-specific humanized mAbs are already available and have been tested in human cancers.