Monoclonal Antibody Therapy in B-Cell CLL

简介(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细胞淋巴样恶性肿瘤的临床研究试验的发展。俄亥俄州立大学血液和肿瘤学分部投入大量资源开发实验治疗计划，特别侧重于单抗和其他生物治疗，并拥有为这些化合物的I/II期试验执行临床和相关实验室研究的专业知识和设施。在B-CLL的治疗中加入单抗尤为关键，因为细胞毒性化疗是不能治愈的。具有不同抗原靶点的新抗体正在进行B-CLL的临床前和临床试验，未来几年的主要挑战将是确定将这些药物与传统疗法相结合的最有效和最安全的方法。这笔赠款主要用于在B-CLL中使用抗CD20抗体利妥昔单抗和抗人类白细胞抗原DR抗体Huld 10的I/II期临床试验。这两种抗体在体外都能诱导B-CLL细胞凋亡，本课题组的初步数据表明，在体内实现了凋亡，并可能与治疗反应有关。此外，D10抗原密度似乎与Huld 10的清除率和临床反应相关。所有患者都会复发，肿瘤对抗体治疗的耐药机制尚不清楚，p53突变在B-CLL中传递耐药表型，而利妥昔单抗对p53缺失细胞无效。然而，黄烷醇通过不依赖于P53的途径诱导细胞凋亡，并可能针对对利妥昔单抗耐药的细胞。这项拨款将检验两个假设：1)黄吡啶、氟达拉滨和利妥昔单抗联合治疗B-CLL将促进细胞凋亡，是一种安全有效的治疗方案。2)HulD10治疗CLL是安全有效的，可能代表了一种可根据肿瘤细胞表面抗原密度给药的抗体。将对患者进行基因分型，以确定这些疗法是否对具有高危特征的患者有效，并值得在该组进行进一步研究。将进行评估肿瘤耐药因素的相关研究，为未来抗体和联合方案的开发提供洞察力。

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.