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，尽管在化疗和免疫治疗方面取得了巨大进展。所有MM患者都有先前的无症状阶段，主要包括意义不明的单克隆丙种球蛋白病（MGUS），随后通常发展为更严重的疾病，称为阴燃MM（SMM）。MGUS患者，尤其是SMM患者，转化为明显的MM，并且没有治疗方法可用于防止其进展为MM。因此，这是开发MGUS和SMM的化学和/或免疫预防策略的未满足的需求。Dickkopf-1（DKK 1）可能是一个很好的目标。DKK 1不存在于包括正常骨髓（BM）浆细胞的正常组织中，但在来自MGUS和SMM患者的BM浆细胞中高度表达，并且它们的表达在MM细胞中进一步升高。我们的研究表明，DKK 1是一个很好的肿瘤相关抗原（TAA），DKK 1疫苗在体内对已建立的MM有治疗作用。该项目的目的是首次确定通过疫苗靶向DKK 1用于免疫预防MM发展的潜力。这项工作将支持MGUS或SMM患者的新型免疫基础，毒性（比化疗）更低的治疗方法的临床开发，以防止进展为明显的MM.完成这些研究是非常重要的和临床上有影响力的，因为DKK 1特异性人源化mAb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.