Radioimmunotherapy for Multiple Myeloma

多发性骨髓瘤的放射免疫治疗

• 批准号: 8306347
• 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/8306347
• 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（申请人提供）：摘要：尽管最近引入了多发性骨髓瘤（MM）的新型新型疗法，但该疾病仍然无法治愈。对于目前在美国的66,000名患者而言，预计诊断只有四年的平均生存率。高剂量的化学疗法，然后进行自体干细胞移植（ASCT）导致完全缓解的速度增加和延长的无疾病生存期，但复发仍然不可避免。对于高剂量的放射免疫疗法（RIT）条件，有一个科学上令人信服的理由，然后是干细胞救援MM。当将急性白血病和B细胞淋巴瘤的自体和同种异体干细胞移植条件方案纳入自体和同种异体干细胞移植方案时，高剂量RIT已表现出功效。预先构成的RIT（PRIT）代表了进一步的完善，可以有效避免常规一步RIT的主要药代动力学局限性，并大大提高肿瘤靶向的特异性。在鼠MM异种移植模型中的初步研究表明，具有放射性标记的抗CD38（OKT10）单克隆抗体的靶标准器官比率良好，并表明抗CD38链霉素（SA）融合蛋白（SA）融合蛋白（OKT10 [SCFV] [SCFV] 4SA 4SA）PRIT会导致改进的治疗指数。该项目旨在确定OKT10 RIT（AIM 1）和OKT10 PRIT（AIM 2）的最佳方案；比较RIT和PRIT药代动力学，生物分布和剂量法以识别出色的方法；进行涉及鼠MM肿瘤异种移植和SCID-HU模型的治疗研究（AIM 3）；并在I期临床试验中评估骨髓性OKT10 RIT或PRIT作为ASCT之前的条件的安全性和可行性。这些研究将由医学博士Damian J. Green（Oliver W. Press，M.D。，Ph.D.）的指导下进行，他拥有一项既定且资助丰富的研究计划，翻译RIT研究的广泛专业知识以及非常成功的指导初级教职员工，以实现全部职业独立。指导的职业发展支持将为绿色专业知识提供有效地转化为临床前发现为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提供的卓越资源。在一起，博士。 Green和Press已正式制定了职业发展计划，该计划详细介绍了统计学，流行病学，生物伦理学，药物开发和免疫学方面的教学研究生培训的结合；动手临床试验设计和管理经验；培训以在各种实验室技术中建立高级技能；并且，定期安排的审查过程，以确保与既定基准的生产力相关的进展。格林博士的研究项目代表了他先前的翻译工作的逻辑扩展，也代表了这位年轻研究者为MM开发新疗法的激动人心的机会。通过越来越多的自治的过程，格林博士将继续完全独立，希望他能够在五年内申请竞争性RO1资金，并成为RIT，MM和干细胞移植领域的领导者。 公共卫生相关性：项目叙述：被诊断患有多发性骨髓瘤的患者，是美国第二常见的血液癌，平均在诊断后仅四年，无法治愈标准治疗。干细胞或骨髓移植可能会延长生存期，但该疾病几乎总是恢复。该项目旨在开发一种新方法，对白血病和淋巴瘤患者的有效有效，该方法直接靶向具有小放射性颗粒的多个骨髓瘤细胞，以选择性地破坏它们。