Molecularly Targeted Therapy for Lymphoma

描述（由申请人提供）：淋巴瘤折磨超过70，000人，每年在美国有1/47的终身风险，但尽管有改进的治疗方案，大多数人会死于他们的疾病。放射治疗仍然是唯一最有效的治疗方法， 局部淋巴瘤，但在多灶性疾病部位的患者中，将吸收剂量递增至治愈水平的能力受到非靶器官毒性的限制。Gopal博士在过去的15年里一直在评估，翻译和优化分子靶向放射免疫疗法（RIT）用于治疗淋巴瘤，并获得了良好的资助和认可。他是第一个提出并确认肿瘤抗原竞争靶向问题的人，并领导了基于RIT的淋巴瘤移植的P01项目。这个K24职业中期研究者奖以患者为导向的研究（POR）将利用Gopal博士在淋巴瘤和RIT方面的专业知识，他作为血液学恶性肿瘤临床研究主任的领导能力，他作为血液学恶性肿瘤数据库和组织采集方案的主要研究者的角色，以及他成功的指导记录，沿着他的中心广泛的基础设施，以促进下一代的发展， 淋巴瘤、恶性血液病和干细胞移植患者导向研究的研究者。他将把50%的时间花在POR的辅导上。目的1将专门评价循环利妥昔单抗阻断CD 20的可能性，并通过详细的剂量测定分析研究2种方法来规避这一挑战。第二个目标将确定自体干细胞移植前给予清髓性剂量的抗CD 45 RIT作为治疗难治性淋巴瘤的方法的临床影响，并将结局与肿瘤部位的吸收剂量相关联。目的3将评估通过“大剂量”抗CD 20 RIT在降低强度同种异体移植后提供改善的无病生存的移植前疾病控制的能力。在目标4中，Gopal博士假设使用RIT进行的淋巴结照射可以提供有益的免疫调节作用，并通过比较CD 20和CD 45对淋巴细胞亚群的靶向作用，以及评价炎性细胞因子和移植物抗宿主病来测试这一前提。这些项目将为肿瘤学学员的POR指导以及相关核医学和血液病理学研究员的共同指导提供充足的机会，以帮助确保下一代临床科学家的成功。

DESCRIPTION (provided by applicant): Lymphoma afflicts over 70,000 individuals each year in the United States with a 1 in 47 lifetime risk, yet despite improved therapeutic options, most will die of their disease. Radiation remains the single most effective therapy for the treatment of localized lymphoma, but the ability to escalate the absorbed dose to curative levels in patients with multifocal sites of disease is limited by non-target organ toxicity. Dr. Gopal has spent the last 15 years evaluating, translating, and optimizing the use of molecularly targeted radioimmunotherapy (RIT) for the treatment of lymphoma and has been well funded and recognized for his work. He was the first to propose and confirm and problem of competitive targeting of tumor antigens and leads a P01 project on RIT based transplantation for lymphoma. This K24 Midcareer Investigator Award in Patient-Oriented Research (POR) will capitalize on Dr. Gopal's expertise in lymphoma and RIT, his leadership as the Director of Clinical Research in Hematologic Malignancies, his role as principal investigator on the hematologic malignancy database and tissue acquisition protocol, and his successful track record of mentoring along with the extensive infrastructure at his center to foster the development of the next generation of investigators in patient oriented research in lymphoma, hematologic malignancies, and stem cell transplantation. He will devote 50% of his time to mentoring in POR. Aim 1 will specifically evaluate the potential for circulating rituximab blocking of CD20 and investigate 2 methods to circumvent this challenge with the readout via detailed dosimetry analysis. The second Aim will determine the clinical impact of delivering myeloablative doses of anti-CD45 RIT prior to autologous stem cell transplantation as a method to treat refractory lymphoma and correlate outcomes with absorbed doses to tumor sites. Aim 3 will evaluate ability of pre-transplant disease control by means of 'mega-dose' anti-CD20 RIT to afford improved disease-free survival after reduced intensity allogeneic transplantation. In Aim 4 Dr. Gopal hypothesizes that the nodal irradiation delivered with RIT could provide a beneficial immunomodulatory effect and tests this premise by comparing CD20 and CD45 targeting on lymphocyte subsets, and evaluating inflammatory cytokines, and graft-versus host disease. These projects will provide an ample opportunity for POR mentoring of oncology trainees as well as co-mentoring of related nuclear medicine and hematopatholgy fellows to help ensure the success of the next generation of clinical scientists.