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

用 DNA 疫苗靶向 DKK1 预防多发性骨髓瘤的发展

基本信息

批准号：
10874135
负责人：
Xiangwei Wu
金额：
$ 110.15万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-26 至 2025-12-25
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10874135
关键词：
Adjuvant Aftercare Agonist Animals Behavior Benign Bone Marrow Cell Line Cells Clinical Clonal Expansion Contractor DNA DNA Vaccines Detection Development Disease Dose Evolution Goals Human Immune Immune response Immunity Immunocompetent Immunoprevention Immunotherapy Injections Malignant - descriptor Malignant Neoplasms Methods Modeling Monoclonal Antibodies Monoclonal gammopathy of uncertain significance Multiple Myeloma Mus Normal tissue morphology OX40 Patients Plasma Cells Prevention Preventive Proteins Regimen Relapse Resistance Risk Serum Spleen Testing Therapeutic Time Tumor Antigens Tumor Burden Vaccinated Vaccines Work cancer cell chemotherapy clinical development design efficacy evaluation experience improved in vivo lymph nodes multiple myeloma M Protein neoplastic cell novel novel strategies prevent tumor vaccine development vaccine efficacy

项目摘要

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.

尽管化疗和免疫疗法取得了巨大进步，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 患者都有前期无症状阶段，主要包括意义未明的单克隆丙种球蛋白病 (MGUS)，随后通常会发展为更严重的病症，称为冒烟型 MM (SMM)。 MGUS 患者，尤其是 SMM 患者，会转化为明显的 MM，并且没有可用的治疗方法来阻止其进展为 MM。因此，开发针对 MGUS 和 SMM 的化学和/或免疫预防策略的需求尚未得到满足。 Dickkopf-1 (DKK1) 可能是实现此目的的绝佳靶标。 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，并且其表达在 MM 细胞中进一步升高。我们的研究表明，DKK1 是一种优秀的肿瘤相关抗原 (TAA)，DKK1 疫苗对体内已形成的 MM 具有治疗作用。该项目的目标是首次确定疫苗靶向 DKK1 用于免疫预防 MM 发展的潜力。这项工作将支持针对 MGUS 或 SMM 患者的新型基于免疫、毒性较低（比化疗）的治疗方法的临床开发，以防止进展为明显的 MM。完成这些研究具有非常重要的临床意义，因为 DKK1 特异性人源化单克隆抗体已经上市，并且已经在人类癌症中进行了测试。