Molecularly Targeted Therapy for Lymphoma

淋巴瘤分子靶向治疗

• 批准号: 8676174
• 负责人: Ajay Gopal
• 金额: $ 17.49万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-18 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676174
• 关键词: 90Y; Address; Allogenic; American; Antibodies; Area; Autologous; Autologous Stem Cell Transplantation; B-Cell Lymphomas; B-Lymphocytes; Cessation of life; Clinical; Clinical Research; Contracts; Databases; Development; Diagnosis; Discipline of Nuclear Medicine; Disease; Disease-Free Survival; Disorder by Site; Dose; Ensure; Environment; Exposure to; Fostering; Funding; Goals; Health; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Homologous Transplantation; Immunobiology; Individual; Inflammatory; Leadership; Lymphatic Irradiation; Lymphocyte; Lymphocyte Subset; Lymphoma; MS4A1 gene; Mentors; Mentorship; Methods; Midcareer Investigator Award in Patient-Oriented Research; Molecular Target; Morbidity - disease rate; Nodal; Organ; Outcome; PTPRC gene; Patients; Population; Principal Investigator; Protocols documentation; Radiation; Radiation Tolerance; Radioimmunotherapy; Recurrent disease; Refractory; Refractory Disease; Relapse; Research; Research Infrastructure; Research Personnel; Research Proposals; Role; Safety; Scientist; Site; Societies; Stem cell transplant; Supportive care; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic effect; Training Support; Translating; Transplant-Related Disorder; Transplantation; Tumor Antigens; United States; United States National Institutes of Health; Work; base; cytokine; cytotoxic; disorder control; dosimetry; effective therapy; graft vs host disease; improved; innovation; irradiation; leukemia/lymphoma; lifetime risk; method development; neoplastic; next generation; novel; oncology; patient oriented; patient oriented research; pre-clinical; programs; radiation absorbed dose; rituximab; success; treatment duration; tumor

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.

描述（由申请人提供）：在美国，每年有超过 70,000 人罹患淋巴瘤，每 47 人中就有 1 人罹患淋巴瘤，尽管治疗方案有所改善，但大多数人仍会死于该病。放射仍然是治疗以下疾病最有效的单一疗法 局限性淋巴瘤，但在多灶性病变患者中将吸收剂量提升至治疗水平的能力受到非靶器官毒性的限制。 Gopal 博士在过去 15 年里一直致力于评估、转化和优化分子靶向放射免疫疗法 (RIT) 在淋巴瘤治疗中的应用，并因其工作获得了充足的资助和认可。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。 K24 面向患者的研究 (POR) 中的职业中期研究者奖将利用 Gopal 博士在淋巴瘤和 RIT 方面的专业知识、他作为血液恶性肿瘤临床研究主任的领导能力、他作为血液恶性肿瘤数据库和组织采集首席研究员的作用协议，以及他成功的指导记录以及他的中心广泛的基础设施，以促进下一代的发展 淋巴瘤、血液恶性肿瘤和干细胞移植领域以患者为导向的研究的研究者。他将投入 50% 的时间来指导 POR。目标 1 将专门评估循环利妥昔单抗阻断 CD20 的潜力，并研究通过详细的剂量测定分析读数来规避这一挑战的 2 种方法。第二个目标将确定在自体干细胞移植之前提供清髓剂量的抗 CD45 RIT 作为治疗难治性淋巴瘤的方法的临床影响，并将结果与​​肿瘤部位的吸收剂量相关联。目标 3 将评估通过“大剂量”抗 CD20 RIT 进行移植前疾病控制的能力，以在降低强度的同种异体移植后改善无病生存。在目标 4 中，Gopal 博士假设 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 CD20 和 CD45 对淋巴细胞亚群的靶向作用、评估炎症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实习生的 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。