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.

项目摘要 /摘要 - 项目3 大多数多发性骨髓瘤（MM）的患者最终死于进行性疾病目的地的高率 对新型代理的最初反应。最近的进步使患有标准风险MM的患者可以预期中位数 诊断为7年以上的生存，但是那些具有高风险疾病特征的人继续经历 早期接力和死亡。尽管自体造血细胞移植（HCT）仍然是护理标准，但 这种干预不能改善HCT风险特征预测的结果的差异。相比之下， 高危特征无法预先确定同种异体HCT之后观察到的响应。骨髓 调节方案与移植物伴有肌瘤作用一致，已经治愈了一些MM的患者，但 参与的毒性和非释放死亡率（NRM）的高率有限。最小化 NRM与高强度准备方案，降低强度调节（RIC）相关的风险 已经引入了方案。但是，RIC后的复发仍然是死亡的主要原因，并采取了措施 应该探讨可以安全地提高调理方案的效率。无线电的敏感性 恶性血浆细胞已被充分记录，并且与高风险骨髓相关的预后不良 细胞遗传学不能预测对放射治疗的反应。 CD38抗原靶向α-Emitter 放射免疫疗法（RIT）可以消除临床前MM模型中的疾病。基于身体 发射α的放射线和利用其潜力的新机会的特征，有一个引人注目的 采用α-发射器RIT治疗MM的理由。 α-Emitter Astatine-211（211AT）沉积了很大的 在几个细胞直径（50-90μm）内的能量（〜100 keV/μm），导致无法弥补的双链DNA 打破了淹没细胞修复机制。该应用的目的是整合α-Emitter RIT 将CD38（211AT-OKT10-B10）靶向同种异体HCT条件，以改善预后 毒性和NRM。该项目将解决三个假设：1）。 211AT-OKT10-B10将是安全且耐受性的 当整合到同种异体HCT调节方案中时2）。 211AT-OKT10-B10将有选择地针对所有 恶性血浆细胞不论突变状态，3）。 B细胞成熟抗原（BCMA）靶向 211AT-BCMA-B10将代表靶向的进一步完善，这将证明临床前小鼠的效率 型号。