Monoclonal Antibody Therapy in B-Cell CLL.

描述（由申请人提供）：林博士的学术和临床兴趣集中在慢性淋巴细胞白血病（B-CLL）和其他惰性B细胞淋巴恶性肿瘤治疗的临床研究试验的发展。 俄亥俄州的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疗法，并拥有专业知识和设施来进行这些化合物的I/II期试验的临床和相关实验室研究。 将单克隆抗体纳入B-CLL的治疗尤其重要，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将这些药物与常规治疗相结合的最有效和最安全的方法。 该资助重点是在B-CLL中使用抗CD 20抗体Rituximab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，体内细胞凋亡是实现的，可能与对治疗的反应相关。 此外，D10抗原密度似乎与HulD 10清除率和临床应答相关。 所有患者都不可避免地复发，并且对抗体治疗的肿瘤抗性机制知之甚少，p53突变在B-CLL中传达抗性表型，并且利妥昔单抗对p53缺陷细胞无效。 然而，flavopiridol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。 该基金将检验2个假设：1）flavopiridol，fludarabine和Rituximab的组合将增强细胞凋亡，是B-CLL的安全有效的治疗方案。 2)HulD 10在CLL中将是安全和有效的，并且可以代表可以基于肿瘤细胞上的抗原密度给药的抗体。 将对患者进行基因亚型分型，以确定这些疗法是否在具有高风险特征的患者中显示疗效，并保证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。

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.