Radioimmunotherapy for Multiple Myeloma

摘要：尽管最近引入了新的有效的治疗多发性骨髓瘤（MM）的新方法，但这种疾病仍然无法治愈。目前美国有6.6万名患者，预计从确诊起平均只能存活4年。高剂量化疗后自体干细胞移植（ASCT）可提高完全缓解率和延长无病生存期，但复发仍然不可避免。高剂量放射免疫治疗（RIT）配合干细胞抢救治疗多发性骨髓瘤有一个令人信服的科学依据。在急性白血病和b细胞淋巴瘤的自体和异体干细胞移植治疗方案中，高剂量RIT已被证明是有效的。预靶向RIT （PRIT）是一种进一步的改进，它可以有效地规避传统一步RIT的主要药代动力学限制，并显着提高肿瘤靶向的特异性。在小鼠MM异种移植模型中的初步研究表明，放射标记的抗cd38 （OKT10）单克隆抗体具有良好的靶器官与正常器官的比例，并且表明抗cd38链亲和素（SA）融合蛋白（OKT10[scFv]4SA） PRIT可以改善治疗指数。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两种方法的药代动力学、生物分布和剂量学；进行小鼠MM肿瘤异种移植和SCID-hu模型的治疗研究（目的3）；并在I期临床试验中评估骨髓清除性OKT10 RIT或PRIT作为ASCT前调节的安全性和可行性。这些研究将由Damian J. Green医学博士在一位杰出的导师（Oliver W. Press，医学博士）的指导下进行，他有一个成熟的、资金充足的研究项目，在RIT转化研究方面拥有广泛的专业知识，并在指导初级教师完全职业独立方面有着非常成功的记录。指导职业发展支持将为格林博士提供将临床前发现有效转化为MM患者临床试验的专业知识。该项目利用了Fred Hutchinson癌症研究中心和华盛顿大学的特殊资源。在一起,Drs。Green和Press已经正式制定了一项职业发展计划，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教学研究生培训的组合；有临床试验设计和管理经验；培训学生掌握各种实验室技术的先进技能；并且，一个定期安排的审查过程，以确保与已建立的生产力基准相关的进展。格林博士的研究项目是他之前的翻译工作的合理延伸，也是这位年轻研究者开发MM新疗法的一个令人兴奋的机会。通过增加自主权的过程，格林博士将完全独立，并期望他能够在五年内为他正在进行的翻译研究申请有竞争力的RO1资金，并成为RIT领域的领导者。骨髓移植和干细胞移植。

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.