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.
