Radioimmunotherapy for Multiple Myeloma

描述（由申请人提供）：摘要：尽管最近推出了新的和有效的新型治疗多发性骨髓瘤（MM），这种疾病仍然无法治愈。对于目前在美国受影响的66，000人来说，预计从诊断开始的平均生存期只有四年。大剂量化疗后自体干细胞移植（ASCT）导致完全缓解率增加和无病生存期延长，但复发仍不可避免。有一个科学的令人信服的理由，高剂量的放射免疫治疗（RIT）预处理后，干细胞救援MM。高剂量RIT已被证明是有效的，当纳入自体和同种异体干细胞移植预处理方案的急性白血病和B细胞淋巴瘤。预靶向RIT（PRIT）代表了进一步的改进，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已证明放射性标记的抗CD 38（OKT 10）单克隆抗体具有良好的靶器官与正常器官比率，并表明抗CD 38链霉亲和素（SA）融合蛋白（OKT 10 [scFv]4SA）PRIT将导致治疗指数改善。本项目旨在确定OKT 10 RIT（目标1）和OKT 10 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，以确定上级方法;进行小鼠MM肿瘤异种移植和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OKT 10 RIT或PRIT作为ASCT前预处理的安全性和可行性。这些研究将由Damian J.绿色，医学博士，在一位杰出导师的指导下（奥利弗W. Press，M.D.，博士）他拥有一个成熟的、资金充足的研究项目，在翻译RIT研究方面拥有广泛的专业知识，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。指导的职业发展支持将为绿色博士提供专业知识，将临床前发现有效地转化为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。绿色博士和出版社一起正式制定了一个职业发展计划，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;动手临床试验设计和管理经验;建立广泛实验室技术先进技能的培训;以及定期进行检讨，以确保在既定的生产力基准方面取得进展。绿色博士的研究项目代表了他先前翻译工作的逻辑延伸，也是这位年轻研究者开发MM新疗法的令人兴奋的机会。绿色博士将继续完全独立，期望他将能够在五年内为他正在进行的转化研究申请有竞争力的RO 1资金，并成为该领域的领导者RIT，MM和干细胞移植的研究。

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.