Monoclonal Antibody Therapy in B-Cell CLL

B 细胞 CLL 的单克隆抗体治疗

• 批准号: 6777334
• 负责人: Thomas S Lin
• 金额: $ 13.18万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777334
• 关键词: B lymphocyte; antineoplastics; apoptosis; chronic lymphocytic leukemia; clinical research; clinical trial phase I; clinical trial phase II; combination therapy; drug resistance; flavopiridol; fludarabine; genetic susceptibility; genotype; human subject; human therapy evaluation; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer pharmacology; neoplastic cell; patient oriented research; pharmacogenetics; pharmacokinetics; tumor antigens

DESCRIPTION (provided by applicant): Dr. Lin's academic and clinical interests are focused on the development of clinical research trials for the treatment of chronic lymphocytic leukemia (B-CLL) and other indolent B-cell lymphoid malignancies. The Division of Hematology and Oncology at Ohio State has devoted significant resources to development of an Experimental Therapeutics Program, with particular emphasis on monoclonal antibodies and other biological therapies, and has the expertise and facilities to perform clinical and correlative laboratory studies for phase I/II trials of these compounds. Incorporation of monoclonal antibodies into treatment of B-CLL is especially critical, as cytotoxic chemotherapy is not curative. New antibodies, with different antigen targets, are in preclinical and clinical trials in B-CLL, and a primary challenge over the next several years will be identifying the most effective and safest ways to combine these agents with conventional therapy. This grant focuses on phase I/II clinical trials using the anti-CD20 antibody Rituximab and the anti-HLA-DR antibody HulD 10 in B-CLL. Both antibodies induce apoptosis in vitro in B-CLL cells, and preliminary data from our group indicate that in vivo apoptosis is achieved and may correlate with response to therapy. In addition, D10 antigen density appears to correlate with the rate of HulD 10 clearance and clinical response. All patients invariably relapse, and mechanisms of tumor resistance to antibody therapy are poorly understood, p53 mutations convey a resistant phenotype in B-CLL, and Rituximab is ineffective against p53-deficient cells. However, flavopiridol induces apoptosis by a p53-independent pathway and may target cells resistant to Rituximab. This grant will test 2 hypotheses: 1) The combination of flavopiridol, fludarabine and Rituximab will enhance apoptosis and be a safe and effective treatment regimen in B-CLL. 2) HulD10 will be safe and effective in CLL and may represent an antibody that can be dosed based upon antigen density on tumor cells. Genetic subtyping of patients will be performed to determine if these therapies show efficacy in patients with high-risk features and warrant further study in this group. Correlative studies to assess tumor resistance factors will be conducted, to provide insight for development of future antibodies and combination regimens.

描述（由申请人提供）：林博士的学术和临床兴趣集中于开发治疗慢性淋巴细胞白血病（B-CLL）和其他惰性 B 细胞淋巴恶性肿瘤的临床研究试验。 俄亥俄州立大学血液学和肿瘤学部门投入了大量资源来开发实验治疗计划，特别强调单克隆抗体和其他生物疗法，并拥有进行 I/II 期临床和相关实验室研究的专业知识和设施这些化合物的试验。 将单克隆抗体纳入 B-CLL 治疗尤为重要，因为细胞毒性化疗无法治愈。 具有不同抗原靶标的新抗体正处于 B-CLL 的临床前和临床试验中，未来几年的主要挑战将是确定将这些药物与常规疗法相结合的最有效和最安全的方法。 该资助重点关注使用抗 CD20 抗体 Rituximab 和抗 HLA-DR 抗体 HulD 10 在 B-CLL 中进行的 I/II 期临床试验。 两种抗体均在体外诱导 B-CLL 细胞凋亡，我们小组的初步数据表明体内细胞凋亡已实现，并且可能与治疗反应相关。 此外，D10 抗原密度似乎与 HulD 10 清除率和临床反应相关。 所有患者都会复发，而且肿瘤对抗体治疗的耐药机制知之甚少，p53 突变在 B-CLL 中表达耐药表型，而利妥昔单抗对 p53 缺陷细胞无效。 然而，flavopiridol 通过 p53 独立途径诱导细胞凋亡，并可能靶向对 Rituximab 耐药的细胞。 这笔资助将测试 2 个假设：1）黄酮吡醇、氟达拉滨和利妥昔单抗的组合将增强细胞凋亡，是 B-CLL 的安全有效的治疗方案。 2) HulD10 在 CLL 中是安全有效的，并且可能代表一种可以根据肿瘤细胞上的抗原密度来给药的抗体。 将对患者进行基因亚型分析，以确定这些疗法是否对具有高风险特征的患者有效，并值得在该组中进行进一步研究。 将进行评估肿瘤耐药因素的相关研究，为未来抗体和联合治疗方案的开发提供见解。