Project 3: Integrating Plasma Cell-Specific Radioimmunotherapy into Allogeneic Stem Cell Transplantation for Myeloma

项目摘要/摘要--项目3 大多数多发性骨髓瘤(MM)患者最终死于进展性疾病，尽管发病率很高 对新药的初步反应。最近的进展使标准风险MM患者能够预测中位数 从确诊之日起存活超过7年，但那些具有高风险疾病特征的人继续经历 早期复发和死亡。尽管自体造血细胞移植(HCT)仍然是一项标准的护理， 这种干预并不能改善HCT前风险特征所预测的结局差异。相比之下， 异基因血细胞移植后观察到的反应不能由高危特征预先确定。清髓剂 结合移植物抗骨髓瘤效应的调理疗法已经治愈了一些多发性骨髓瘤患者，但 伴随而来的毒性和高无复发死亡率(NRM)限制了其广泛应用。要最小化 与高强度准备方案、低强度预适应(RIC)相关的NRM的风险 已经引入了养生法。然而，RIC后复发仍然是主要的死亡原因，并采取措施 是否可以安全地提高调理方案的疗效有待探索。它的辐射敏感性 恶性浆细胞已有很好的文献记载，预后不良与高危骨髓有关。 细胞遗传学不能预测对放射治疗的反应。α发射体靶向CD38抗原的研究 放射免疫治疗(RIT)可以消除临床前MM模型中的疾病。基于物理的 发射α的放射性核素的特点和利用其潜力的新机会，具有令人信服的 使用α发射区RIT治疗MM的理论基础α发射区-211(211 At)沉积了大量的 能量(~100keV/μm)在几个细胞直径(50-90μm)内产生不可修复的双链dna 压倒细胞修复机制的断裂。此应用程序的目的是集成α-发射器RIT 靶向CD38(211At-OKT10-B10)进入同种异体红细胞移植预适应在不增加的情况下改善预后 毒性和NRM。该项目将解决三个假设：1)。211At-OKT10-B10将是安全和耐受性良好的 当整合到同种异体血细胞移植调理方案中时2)。211At-OKT10-B10将选择性地针对所有 恶性浆细胞，与突变状态无关，3)。靶向B细胞成熟抗原(BCMA) 211At-BCMA-B10将代表靶向的进一步改进，将在临床前小鼠中展示有效性 模特们。

PROJECT SUMMARY / ABSTRACT – Project 3 The majority of patients with multiple myeloma (MM) ultimately die of progressive disease despite high rates of initial response to novel agents. Recent advances allow patients with standard-risk MM to anticipate a median survival of over 7 years from diagnosis, however those with high-risk disease features continue to experience early relapse and death. Although autologous hematopoietic cell transplant (HCT) remains a standard of care, this intervention does not ameliorate the differences in outcome predicted by pre-HCT risk features. In contrast, responses observed after allogeneic HCT cannot be predetermined by high-risk features. Myeloablative conditioning regimens, in concert with a graft-versus-myeloma effect, have cured some patients with MM, but the accompanying toxicity and high rates of non-relapse mortality (NRM) have limited wide adoption. To minimize the risk of NRM associated with high-intensity preparative regimens, reduced-intensity conditioning (RIC) regimens have been introduced. Relapse after RIC however, remains the leading cause of death, and measures that can safely improve the efficacy of the conditioning regimen should be explored. The radio-sensitivity of malignant plasma cells has been well documented, and the poor prognosis associated with high-risk marrow cytogenetics is not predictive of response to radiation therapy. CD38 antigen-targeting with α-emitter radioimmunotherapy (RIT) can eliminate disease in pre-clinical MM models. Based on the physical characteristics of α-emitting radionuclides and new opportunities to harness their potential, there is a compelling rationale for employing α-emitter RIT to treat MM. The α-emitter astatine-211 ( 211At) deposits a very large amount of energy (~100 keV/μm) within a few cell diameters (50-90 μm) resulting in irreparable double strand DNA breaks that overwhelm cellular repair mechanisms. The purpose of this application is to integrate α-emitter RIT targeting CD38 (211At-OKT10-B10) into allogeneic HCT conditioning to improve outcomes without increasing toxicity and NRM. The project will address three hypotheses: 1). 211At-OKT10-B10 will be safe and well tolerated when integrated into an allogeneic HCT conditioning regimen 2). 211At-OKT10-B10 will selectively target all malignant plasma cells irrespective of mutational status, 3). B cell maturation antigen (BCMA) targeting with 211At-BCMA-B10 will represent a further refinement to targeting that will demonstrate efficacy in preclinical mouse models.