Monoclonal Antibody Therapy in B-Cell CLL

简介（由申请人提供）：林博士的学术和临床兴趣主要集中在慢性淋巴细胞白血病（B-CLL）和其他惰性b细胞恶性肿瘤的临床研究试验的发展。俄亥俄州立大学血液学和肿瘤学部门投入了大量资源开发实验治疗项目，特别强调单克隆抗体和其他生物治疗，并拥有专业知识和设施，为这些化合物的I/II期试验进行临床和相关实验室研究。结合单克隆抗体治疗B-CLL尤其重要，因为细胞毒性化疗不能治愈。具有不同抗原靶点的新抗体正在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最有效和最安全的方法将这些药物与传统疗法结合起来。这笔拨款的重点是在B-CLL中使用抗cd20抗体利妥昔单抗和抗hla - dr抗体HulD 10的I/II期临床试验。这两种抗体在体外诱导B-CLL细胞凋亡，我们小组的初步数据表明，体内细胞凋亡可以实现，并且可能与对治疗的反应有关。此外，D10抗原密度似乎与hld - 10清除率和临床反应相关。所有患者都不可避免地复发，肿瘤对抗体治疗的抵抗机制尚不清楚，p53突变在B-CLL中传递了一种耐药表型，利妥昔单抗对p53缺陷细胞无效。然而，黄吡醇通过p53非依赖性途径诱导细胞凋亡，并可能靶向对利妥昔单抗耐药的细胞。该资助将检验2个假设：1)黄匹吡醇、氟达拉滨和利妥昔单抗联合使用将促进细胞凋亡，是B-CLL安全有效的治疗方案。2) HulD10在CLL中是安全有效的，可能代表一种抗体，可以根据肿瘤细胞上的抗原密度来给药。将对患者进行遗传分型，以确定这些疗法是否对具有高危特征的患者有效，并在该组中进行进一步研究。将开展相关研究，评估肿瘤耐药因素，为未来抗体和联合治疗方案的发展提供见解。

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.