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

项目3：将浆细胞特异性放射免疫疗法整合到骨髓瘤的同种异体干细胞移植中

• 批准号: 10442612
• 负责人: Damian J. Green
• 金额: $ 31.6万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-12 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442612
• 关键词: Address; Adoption; Adoptive Immunotherapy; Allogenic; Antibodies; Antigen Receptors; Antigen Targeting; Antigens; Astatine; Autologous; B-Lymphocytes; Biodistribution; Caliber; Cause of Death; Cell Death; Cell Maturation; Cells; Cessation of life; Characteristics; Clinical Trials; Coupling; Cyclophosphamide; Cytogenetics; DNA Double Strand Break; Deposition; Diagnosis; Disease; Dose; Effectiveness; GTP-Binding Protein alpha Subunits, Gs; Intervention; Label; Malignant - descriptor; Malignant Neoplasms; Marrow; Measures; Modeling; Monoclonal Antibodies; Multiple Myeloma; Mus; Patients; Plasma Cells; Preparation; Prognosis; Progressive Disease; Radiation; Radiation Tolerance; Radiation therapy; Radioactivity; Radioimmunotherapy; Radioisotopes; Regimen; Relapse; Risk; Safety; Stem cell transplant; Testing; Toxic effect; Transplantation Conditioning; Treatment Efficacy; Whole-Body Irradiation; Xenograft Model; base; cancer cell; cell injury; chimeric antigen receptor T cells; cohort; conditioning; disorder control; disorder risk; donor stem cell; early experience; fludarabine; gamma secretase; hematopoietic cell transplantation; high risk; improved; improved outcome; inhibitor; mortality; mouse model; mutational status; novel; outcome prediction; post-transplant disease; pre-clinical; prevent; radiation delivery; radiation response; receptor expression; relapse patients; repaired; response; risk minimization; side effect; standard of care

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.

项目概要/摘要-项目3 大多数多发性骨髓瘤（MM）患者最终死于疾病进展，尽管其高发病率。 对新药物的初步反应。最新进展允许标准风险MM患者预期中位 从诊断起生存7年以上，然而，具有高危疾病特征的患者继续经历 早期复发和死亡。虽然自体造血细胞移植（HCT）仍然是护理标准， 这种干预不能改善HCT前风险特征预测的结果差异。与此相反， 同种异体HCT后观察到的反应不能由高风险特征预先确定。清髓 预处理方案与移植物抗骨髓瘤效应相结合，治愈了一些MM患者，但 伴随的毒性和高的非复发死亡率（NRM）限制了广泛采用。以最小化 与高强度准备方案、低强度预处理（RIC）相关的NRM风险 已经采用了一些治疗方案。然而，RIC后复发仍然是死亡的主要原因， 应该探索能够安全地提高预处理方案的功效的方法。放射敏感性 恶性浆细胞已被充分记录，预后不良与高风险骨髓 细胞遗传学不能预测对放射治疗的反应。使用α-发射体靶向CD 38抗原 放射免疫疗法（RIT）可以消除临床前MM模型中的疾病。基于物理 α放射性核素的特性和利用其潜力的新机会， 使用α-发射体RIT治疗MM的基本原理。α-发射体211 At沉积了非常大量的 在几个细胞直径（50-90 μm）内产生不可修复的双链DNA 破坏了细胞修复机制本应用的目的是集成α发射器RIT 靶向CD 38（211 At-OKT 10-B10）进入同种异体HCT预处理，以改善结局，而不增加 毒性和NRM。该项目将解决三个假设：1）。211 At-OKT 10-B10安全且耐受性良好 当整合到同种异体HCT预处理方案中时2）。211 At-OKT 10-B10将选择性地靶向所有 与突变状态无关的恶性浆细胞，3）。靶向B细胞成熟抗原（BCMA）， 211 At-BCMA-B10将代表对靶向的进一步细化，其将在临床前小鼠中证明疗效。 模型