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

尽管化疗和免疫治疗取得了很大进展，但多发性骨髓瘤(MM)仍然是一种无法治愈的浆细胞癌。所有MM患者都有先前的无症状阶段，主要包括未确定意义的单克隆性伽马病(MGUS)，随后通常会发展为更严重的阴燃MM(SMM)。MGUS，尤其是SMM的患者转化为显性MM，目前尚无治疗方法可防止其进展为MM。因此，为MGUS和SMM开发化疗和/或免疫预防策略是一个尚未得到满足的需求。Dickkopf-1(Dkk1)可能是一个很好的靶标。Dkk1在包括正常骨髓浆细胞在内的正常组织中不表达，但在MGUS和SMM患者的BM浆细胞中高表达，在MM细胞中进一步上调。我们的研究表明，Dkk1是一种很好的肿瘤相关抗原(TAA)，Dkk1疫苗对体内已建立的MM具有治疗作用。该项目的目标是首次确定通过疫苗靶向Dkk1的潜力，以用于MM的免疫预防发展。这项工作将支持为MGUS或SMM患者开发新的基于免疫的、毒性较低(比化疗更低)的治疗方法，以防止进展为显性MM。完成这些研究具有非常重要的意义和临床影响，因为Dkk1特异性人源化mAbs已经可以获得，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.