Radioimmunotherapy for Multiple Myeloma

描述(申请人提供)：摘要：尽管最近引入了治疗多发性骨髓瘤(MM)的新的有效的新疗法，但这种疾病仍然无法治愈。美国目前有6.6万名患者，预计确诊后平均只有四年的存活期。大剂量化疗和自体干细胞移植(ASCT)可提高完全缓解率和延长无病生存期，但复发仍是不可避免的。有一个科学上令人信服的理由，即高剂量放射免疫疗法(RIT)预适应，然后对MM进行干细胞拯救。高剂量RIT在急性白血病和B细胞淋巴瘤的自体和异基因干细胞移植预适应方案中均已证明有效。前靶向RIT(PRIT)代表了一种进一步的改进，可以有效地绕过传统一步RIT的主要药代动力学限制，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，放射性标记的抗CD38(OKT10)单抗具有良好的靶器官与正常器官比率，并提示抗CD38链霉亲和素(SA)融合蛋白(OKT10[scFv]4SA)Prit将导致治疗指数的改善。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的药代动力学、生物分布和剂量学，以确定更优的方法；进行涉及小鼠MM肿瘤移植和SCID-Hu模型的治疗研究(AIM 3)；以及在I期临床试验中评估清髓性OKT10 RIT或PRIT作为ASCT之前的预适应的安全性和可行性。这些研究将由Damian J.Green医学博士在一位杰出的导师(Oliver W.Press，M.D.，Ph.D.)的指导下进行。世卫组织拥有成熟且资金充足的研究计划，在翻译RIT研究方面拥有广泛的专业知识，并在指导初级教师实现完全职业独立方面取得了非常成功的记录。指导职业发展支持将为格林博士提供将临床前发现有效地转化为MM患者临床试验的专业知识。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。格林博士和普赖斯博士一起正式制定了职业发展计划，其中详细介绍了统计学、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；实践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；以及定期安排的审查过程，以确保与既定的生产力基准相关的进展。格林博士的研究项目代表了他之前翻译工作的合理扩展，并为这位年轻的研究人员提供了一个为MM开发新疗法的令人兴奋的机会。通过增加自主权的过程，格林博士将走向完全独立，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R01资金，并在十年内成为RIT、MM和干细胞移植领域的领先者。

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 R01 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.