Radioimmunotherapy for Multiple Myeloma

多发性骨髓瘤的放射免疫治疗

• 批准号: 8522264
• 负责人: Damian J. Green
• 金额: $ 16.96万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522264
• 关键词: 90Y; 90Y-DOTA-Biotin; Acute leukemia; Allogenic; Antibodies; Antigens; Autologous; Autologous Stem Cell Transplantation; B-Cell Lymphomas; Behavior; Benchmarking; Biodistribution; Bioethics; Biological; Biological Models; Biotin; Blood; Blood Circulation; Bone Marrow Transplantation; Bortezomib; Cells; Chimeric Proteins; Clinical Trials; Clinical Trials Design; DOTA-biotin; Development Plans; Diagnosis; Disease; Disease remission; Disease-Free Survival; Doctor of Medicine; Doctor of Philosophy; Dose; Drug Kinetics; Ensure; Epidemiology; Faculty; Fred Hutchinson Cancer Research Center; Funding; Hematopoietic Neoplasms; High Dose Chemotherapy; Human; Image; Immunoglobulin G; Immunology; Individual; Kinetics; Laboratories; Life; Malignant - descriptor; Melphalan; Mentors; Methods; Modeling; Monoclonal Antibodies; Multiple Myeloma; Mus; One-Step dentin bonding system; Organ; Patients; Phase I Clinical Trials; Plasma Cells; Population; Positioning Attribute; Process; Productivity; Proteasome Inhibitor; Radiation; Radio; Radioactive; Radioactivity; Radioimmunoconjugate; Radioimmunotherapy; Radiolabeled; Regimen; Relapse; Research; Research Personnel; Research Project Grants; Resources; SCID-hu Mice; Safety; Schedule; Stem cell transplant; Stem cells; Streptavidin; Techniques; Testing; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Training; Translational Research; Translations; Treatment Efficacy; Tretinoin; United States; Universities; Washington; Work; Xenograft Model; Xenograft procedure; abstracting; career; career development; conditioning; design; dosimetry; drug development; expectation; experience; improved; leukemia/lymphoma; mouse model; neoplastic cell; novel; novel strategies; particle; pre-clinical; programs; public health relevance; radiotracer; receptor expression; response; skills; standard care; statistics; tumor specificity; tumor xenograft

DESCRIPTION (provided by applicant): Abstract: Despite the recent introduction of new and effective novel therapies for multiple myeloma (MM), the disease remains incurable. For the 66,000 individuals in United States currently afflicted, an average survival of only four years from diagnosis is anticipated. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) leads to increased rates of complete remission and prolonged periods of disease free survival, but relapse remains inevitable. There is a scientifically compelling rationale for high dose radioimmunotherapy (RIT) conditioning followed by stem cell rescue for MM. High dose RIT has demonstrated efficacy when incorporated into both autologous and allogeneic stem cell transplant conditioning regimens for acute leukemia and B-cell lymphoma. Pretargeted RIT (PRIT) represents a further refinement that can effectively circumvent the major pharmacokinetic limitations of conventional one-step RIT and dramatically improve the specificity of tumor targeting. Initial studies in murine MM xenograft models have demonstrated favorable target-to-normal organ ratios with radiolabeled anti-CD38 (OKT10) monoclonal antibody and suggest that an improved therapeutic index will result with anti-CD38 streptavidin (SA) fusion protein (OKT10[scFv]4SA) PRIT. This project is designed to identify optimal regimens for OKT10 RIT (Aim 1) and OKT10 PRIT (Aim 2); compare RIT and PRIT pharmacokinetics, biodistributions and dosimetry to identify the superior method; perform therapy studies involving murine MM tumor xenograft and SCID-hu models (Aim 3); and evaluate the safety and feasibility of myeloablative OKT10 RIT or PRIT as conditioning prior to ASCT in a Phase I clinical trial. These studies will be performed by Damian J. Green, M.D., under the guidance of an outstanding mentor (Oliver W. Press, M.D., Ph.D.) who has an established and well funded research program, extensive expertise in translational RIT research and a very successful track record of guiding junior faculty to full career independence. Mentored Career Development support will provide Dr. Green expertise in the efficient translation of preclinical discovery into clinical trials for patients with MM. The project takes advantage of the exceptional resources available at the Fred Hutchinson Cancer Research Center and at the University of Washington. Together, Drs. Green and Press have formalized a career development plan that details a combination of didactic postgraduate training in statistics, epidemiology, bioethics, drug development and immunology; hands-on clinical trial design and management experience; training to establish advanced skills in a broad array of laboratory techniques; and, a process of regularly scheduled review to ensure progress in relation to established benchmarks for productivity. Dr. Green's research project represents the logical extension of his prior translational work and an exciting opportunity for this young investigator to develop new therapies for MM. Through a process of increasing autonomy, Dr. Green will proceed to full independence with the expectation that he will be in a position to apply for competitive RO1 funding for his ongoing translational research within five years and become a leader in the field of RIT, MM and stem cell transplantation within a decade. PUBLIC HEALTH RELEVANCE: Project Narrative: Patients diagnosed with multiple myeloma, the second most common blood cancer in the United States, live an average of only four years after diagnoses and cannot be cured with standard treatments. Stem cell or bone marrow transplant may prolong survival, but the disease almost always returns. This project is designed to develop a new approach, already proven effective for patients with leukemia and lymphoma, that directly targets multiple myeloma cells with small radioactive particles to selectively destroy them.

描述（由申请人提供）： 摘要：尽管最近针对多发性骨髓瘤（MM）引入了新的有效疗法，但该疾病仍然无法治愈。美国目前有 66,000 名患者，预计诊断后平均生存期仅为四年。高剂量化疗后进行自体干细胞移植（ASCT）可提高完全缓解率并延长无病生存期，但复发仍然不可避免。对于多发性骨髓瘤，采用高剂量放射免疫治疗 (RIT) 调理，然后进行干细胞拯救，具有令人信服的科学依据。当将高剂量 RIT 纳入针对急性白血病和 B 细胞淋巴瘤的自体和同种异体干细胞移植调理方案时，已显示出疗效。预靶向 RIT (PRIT) 代表了一种进一步的改进，可以有效规避传统一步 RIT 的主要药代动力学限制，并显着提高肿瘤靶向的特异性。小鼠 MM 异种移植模型的初步研究表明，放射性标记的抗 CD38 (OKT10) 单克隆抗体具有良好的靶点与正常器官的比率，并表明抗 CD38 链霉亲和素 (SA) 融合蛋白 (OKT10[scFv] 可以改善治疗指数]4SA) 普里特。该项目旨在确定 OKT10 RIT（目标 1）和 OKT10 PRIT（目标 2）的最佳方案；比较 RIT 和 PRIT 药代动力学、生物分布和剂量测定以确定更好的方法；进行涉及小鼠 MM 肿瘤异种移植物和 SCID-hu 模型的治疗研究（目标 3）；并在 I 期临床试验中评估清髓性 OKT10 RIT 或 PRIT 作为 ASCT 前调理的安全性和可行性。这些研究将由 Damian J. Green 医学博士在一位杰出导师（Oliver W. Press 医学博士、哲学博士）的指导下进行，该导师拥有成熟且资金充足的研究项目、在转化 RIT 研究方面的丰富专业知识以及在指导初级教师实现完全职业独立方面有着非常成功的记录。指导性职业发展支持将为 Green 博士提供专业知识，帮助其将临床前发现有效转化为 MM 患者的临床试验。该项目利用了弗雷德·哈钦森癌症研究中心和华盛顿大学的特殊资源。在一起，博士。格林和普雷斯已经正式制定了职业发展计划，详细说明了统计学、流行病学、生物伦理学、药物开发和免疫学方面的研究生教学培训的结合；实际临床试验设计和管理经验；培训以建立广泛的实验室技术方面的高级技能；定期审查流程，以确保在既定生产力基准方面取得进展。 Green 博士的研究项目代表了他之前的转化工作的逻辑延伸，并且为这位年轻的研究者开发 MM 新疗法提供了令人兴奋的机会。通过增强自主权的过程，Green 博士将走向完全独立，期望他能够在五年内为其正在进行的转化研究申请有竞争力的 RO1 资助，并成为 RIT、MM 领域的领导者十年内进行干细胞移植。 公共健康相关性：项目叙述：被诊断患有多发性骨髓瘤（美国第二大常见血癌）的患者在诊断后平均只能存活四年，并且无法通过标准治疗治愈。干细胞或骨髓移植可以延长生存期，但疾病几乎总是会复发。该项目旨在开发一种新方法，该方法已被证明对白血病和淋巴瘤患者有效，用小放射性粒子直接靶向多发性骨髓瘤细胞，选择性地破坏它们。