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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA102276-02
Application #
6898478
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$131,814
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Lin, Thomas S; Blum, Kristie A; Fischer, Diane Beth et al. (2010) Flavopiridol, fludarabine, and rituximab in mantle cell lymphoma and indolent B-cell lymphoproliferative disorders. J Clin Oncol 28:418-23
Woyach, Jennifer A; Heerema, Nyla A; Zhao, John et al. (2010) Dic(17;18)(p11.2;p11.2) is a recurring abnormality in chronic lymphocytic leukaemia associated with aggressive disease. Br J Haematol 148:754-9
Christian, Beth A; Grever, Michael R; Byrd, John C et al. (2009) Flavopiridol in chronic lymphocytic leukemia: a concise review. Clin Lymphoma Myeloma 9 Suppl 3:S179-85
Phelps, Mitch A; Lin, Thomas S; Johnson, Amy J et al. (2009) Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood 113:2637-45
Lin, Thomas S; Ruppert, Amy S; Johnson, Amy J et al. (2009) Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 27:6012-8
Lin, Thomas S; Stock, Wendy; Xu, Huiping et al. (2009) A phase I/II dose escalation study of apolizumab (Hu1D10) using a stepped-up dosing schedule in patients with chronic lymphocytic leukemia and acute leukemia. Leuk Lymphoma 50:1958-63
Christian, Beth A; Lin, Thomas S (2008) Antibody therapy for chronic lymphocytic leukemia. Semin Hematol 45:95-103
Lin, T S; Flinn, I W; Lucas, M S et al. (2005) Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia. Leukemia 19:1207-10
Lin, T S; Penza, S L; Avalos, B R et al. (2005) Diffuse alveolar hemorrhage following gemtuzumab ozogamicin. Bone Marrow Transplant 35:823-4