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

基本信息

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
项目类别：
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

项目摘要

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 尽管多发性骨髓瘤 (MM) 发病率很高，但大多数患者最终死于进行性疾病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。诊断后生存期超过 7 年，但那些具有高风险疾病特征的人仍会经历尽管自体造血细胞移植（HCT）仍然是一种标准治疗方法，这种干预措施并不能改善 HCT 前风险特征预测的结果差异。同种异体 HCT 后观察到的反应不能通过高风险特征来预测。预处理方案与移植物抗骨髓瘤效应相结合，治愈了一些多发性骨髓瘤患者，但是伴随的毒性和高非复发死亡率（NRM）限制了广泛采用。与高强度准备方案、低强度训练 (RIC) 相关的 NRM 风险然而，RIC 后的复发仍然是死亡的主要原因，因此需要采取措施。应探索可以安全地提高预处理方案的放射敏感性。恶性浆细胞已被充分记录，并且与高风险骨髓相关的不良预后细胞遗传学不能预测 α 发射体靶向 CD38 抗原的反应。放射免疫疗法（RIT）可以消除基于物理的临床前MM模型中的疾病。 α发射放射性核素的特性以及利用其潜力的新机会，有一个令人信服的使用α发射体RIT治疗MM的理由 α发射体砹211（211At）沉积量非常大。几个细胞直径 (50-90 μm) 内的能量 (~100 keV/μm) 导致不可修复的双链 DNA 该应用的目的是整合 α 发射体 RIT。将 CD38 (211At-OKT10-B10) 靶向同种异体 HCT 调节，以改善结果而不增加该项目将解决三个假设：1)。 211At-OKT10-B10 将选择性地瞄准所有恶性浆细胞，无论突变状态如何，3) 靶向 B 细胞成熟抗原 (BCMA)。 211At-BCMA-B10 将代表对靶向的进一步细化，将在临床前小鼠中证明功效模型。