Anti-CD38 targeted alpha emitter radioimmunotherapy to eliminate multiple myeloma

抗 CD38 靶向 α 发射体放射免疫疗法消除多发性骨髓瘤

基本信息

批准号：
10601435
负责人：
Damian J. Green
金额：
$ 35.62万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-08 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10601435
关键词：
Address Antibodies Antigen Targeting Apoptosis Applications Grants Autologous Stem Cell Transplantation Avidity Behavior Therapy Biological Models Biotechnology Bone Marrow Caliber Cell Death Cells Characteristics Chromosome abnormality Clinical Clinical Trials Clinical Trials Design Clone Cells Coupled DNA Damage DNA Double Strand Break Deposition Disease Disease Progression Dose Dose-Limiting Flow Cytometry Fred Hutchinson Cancer Research Center Goals Health Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms Heterogeneity High Dose Chemotherapy Human In complete remission Individual Investigational New Drug Application Label Lead Length MEL Gene Maintenance Malignant - descriptor Malignant Bone Neoplasm Malignant Neoplasms Marrow Maximum Tolerated Dose Measurement Measures Melphalan Minority Modeling Modification Monoclonal Antibodies Multiple Myeloma Outcome Parents Patients Phase I Clinical Trials Phase II Clinical Trials Plasma Cells Positioning Attribute Preparation Prognosis Progressive Disease Proteins Radiation induced damage Radioactive Radioimmunoconjugate Radioimmunotherapy Radioisotopes Radiolabeled Reagent Recording of previous events Recovery Regimen Relapse Research Research Personnel Residual Neoplasm SCID-hu Mice Sampling Site Stem cell transplant Surface Sweden Testing Therapeutic Index Tissues Toxic effect Transplantation Conditioning United States Food and Drug Administration Universities Washington base chemotherapy conditioning design ds-DNA efficacy evaluation experience high risk immunoreactivity improved innovation mutational status neoplastic cell neovascularization next generation sequencing novel novel strategies patient subsets pre-clinical prevent repaired response skills standard of care targeted imaging treatment response virtual

项目摘要

PROJECT SUMMARY/ABSTRACT The majority of patients with multiple myeloma (MM) ultimately die of progressive disease despite high rates of initial response to novel agents. While complete response (CR) is achievable in a significant subset of patients, most of these individuals relapse as a consequence of minimal residual disease (MRD) defined by occult foci of treatment insensitive tumor cells clones. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves response, but relapse remains virtually inevitable. No modification to high dose melphalan chemotherapy conditioning regimens has further augmented the impact of ASCT on outcome over the past two decades. Unmodified CD38 monoclonal antibodies (MAbs) have demonstrated anti-MM tumor cell responses and CD38 antigen targeting with β-emitter radioimmunotherapy (RIT) can eliminate disease in pre-clinical MM models. In clinical settings however, β-emitter RIT has been associated with dose limiting toxicity that can prevent dose escalation to levels necessary for elimination of MRD in a substantial proportion of patients. 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 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. We anticipate that this combination of high energy and short path length will confer a unique capacity to kill individual targeted MM cells and eliminate MRD with minimal radiation damage to surrounding tissues. This proposal will use 211At to functionalize an anti-CD38 monoclonal antibody ([211At]OKT10-B10) as part of a novel approach to ASCT conditioning. The goal of this project is to address three hypotheses: 1). [211At]OKT10-B10 will eliminate MRD by selectively targeting all malignant plasma cells irrespective of mutational status, 2). [211At]OKT10-B10 will disrupt the disease permissive milieu found in the bone marrow microenvironment of MM patients and 3) [211At]OKT10-B10 will demonstrate a therapeutic index sufficient to safely sterilize all occult sites of disease. First, we will generate clinical grade [211At]OKT10-B10 necessary to perform patient studies. Second, we will conduct a clinical trial to a) demonstrate that [211At]OKT10-B10 localizes to MM target cells as confirmed by direct measurement of 211At in the bone marrow and alpha camera images of target tissue; and b) evaluate the safely of [211At]OKT10-B10 dose escalation in combination with high dose melphalan. Third, we will assess the impact of [211At]OKT10-B10 on a) stringent complete response rates, b) MRD detected by high throughput next generation sequencing and multi-parameter high sensitivity flow cytometry, c) the bone marrow microenvironment, d) MM cell repopulating potential in a SCID-hu model, and e) double strand DNA injury in target cells. The successful elimination of MRD through the incorporation of [211At]OKT10-B10 into ASCT conditioning could lead to significant improvements in MM patient survival and potentially eradicate disease.

项目概要/摘要尽管多发性骨髓瘤 (MM) 发病率很高，但大多数患者最终死于进行性疾病虽然相当一部分患者可以达到完全缓解（CR），这些人中的大多数人由于隐匿病灶定义的微小残留病（MRD）而复发治疗不敏感的肿瘤细胞克隆的高剂量化疗，然后是自体干细胞。移植（ASCT）改善了反应，但复发实际上仍然不可避免。剂量马法兰化疗预处理方案进一步增强了 ASCT 对结果的影响在过去的二十年中，未修饰的 CD38 单克隆抗体 (MAb) 已被证明具有抗 MM 作用。肿瘤细胞反应和 CD38 抗原靶向 β 发射体放射免疫疗法 (RIT) 可以消除然而，在临床前 MM 模型中，β-发射体 RIT 与剂量相关。限制毒性，可防止剂量增加至大量消除 MRD 所需的水平基于α发射放射性核素的身体特征和新机会。为了发挥其潜力，采用 α 发射体 RIT 治疗 MM 具有令人信服的理由。 211At 在几个细胞直径 (50-90 μm) 内沉积大量能量 (~100 keV/μm)，从而导致不可修复的双链 DNA 断裂会压倒细胞修复机制。高能量和短路径长度的结合将赋予杀死单个目标MM的独特能力该提案将使用 211At 来消除 MRD，同时对周围组织造成最小的辐射损伤。将抗 CD38 单克隆抗体 ([211At]OKT10-B10) 功能化，作为 ASCT 新方法的一部分该项目的目标是解决三个假设：1)。通过选择性地靶向所有恶性浆细胞，无论突变状态如何，[211At]OKT10-B10 将。破坏 MM 患者骨髓微环境中发现的疾病许可环境，以及 3) [211At]OKT10-B10 将证明其治疗指数足以安全地消灭所有隐匿的疾病部位。首先，我们将生成进行患者研究所需的临床等级 [211At]OKT10-B10。进行临床试验以 a) 证明 [211At]OKT10-B10 定位于 MM 靶细胞，如通过直接测量骨髓中的 211At 和目标组织的 α 相机图像；以及 b) 评估 [211At]OKT10-B10 剂量递增与高剂量马法兰联合使用的安全性第三，我们将评估。 [211At]OKT10-B10 对 a) 严格的完全缓解率，b) 高通量检测到的 MRD 的影响下一代测序和多参数高灵敏度流式细胞术，c) 骨髓微环境，d) SCID-hu 模型中 MM 细胞的重新增殖潜力，以及 e) 双链 DNA 损伤通过将 [211At]OKT10-B10 纳入 ASCT 成功消除 MRD。调理可以显着提高多发性骨髓瘤患者的生存率并有可能根除疾病。