The central hypothesis of this proposal is that there are chronic lymphocytic leukemia (CLL) associated antigens that can be recognized by host T cells. However, due to the CLL phenotype the T cells that can recognize such antigens may be rendered anergic. Conventional and some novel forms of chemotherapy for this disease may adversely affect anergic T cell that may be capable of responding to CLL-associated antigens. CLL cells can be converted into effective antigen presenting cells via CD40-ligation in vitro. This led to development of strategies for introducing the gene encoding the CD40-ligand (CD154) into CLL cells using recombinant adenovirus vectors, designated AdCD154. We find that CLL cells infected with AdCD154 can induce autologous T cell responses in vitro, leading to generation of cytotoxic T lymphocytes (CTL) against non-modified CLL cells. This served as the basis for a phase I gene therapy trial intended to examine the safety of a single intravenous infusion of autologous AdCD154-CLL cells to patients with intermediate or high-risk disease. The encouraging results from this clinical trial and preliminary in vitro studies support the hypothesis that there are CLL-associated antigens that can be recognized to host T cells and potentially targeted by host CTL, leading to immune clearance of CLL cells. To dissect the spontaneous and induced cellular responses to putative CLL-associated antigens we have the following specific aims. (1) Examine the expressed T cell receptor Vbeta repertoires of blood T cells of patients at diagnosis and pre- and post treatment with therapies developed by the CLL Research Consortium (CRC). (2) Evaluate the precursor frequency of blood T cells at similar time-points that can elaborate interferon-gamma in response to AdCD154-CLL or to autologous CLL cells after CD3/CD28-ligation in vitro. (3) Define peptides encoded by genes implicated in the pathogenesis or progression of CLL by in Project 1 of this proposal that could serve as potential LL- associated antigens. (4) Use T cell lines reactive with autologous CLL cells in strategies that can identify and isolate genes encoding tumor- associated antigens. (5) Develop a phase II CRC trial of gene therapy involving multiple infusion of autologous AdCD154-CLL cells. Through these studies we identify CLL-associated antigens and develop novel forms of immune-based therapies for this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA081534-03S1
Application #
6477412
Study Section
Subcommittee G - Education (NCI)
Project Start
2001-07-11
Project End
2002-04-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
2001
Total Cost
$165,355
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Vangapandu, Hima V; Chen, Huiqin; Wierda, William G et al. (2018) Proteomics profiling identifies induction of caveolin-1 in chronic lymphocytic leukemia cells by bone marrow stromal cells. Leuk Lymphoma 59:1427-1438
Yu, Jian; Chen, Yun; Chen, Liguang et al. (2018) Cirmtuzumab inhibits ibrutinib-resistant, Wnt5a-induced Rac1 activation and proliferation in mantle cell lymphoma. Oncotarget 9:24731-24736
Barr, Paul M; Robak, Tadeusz; Owen, Carolyn et al. (2018) Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica 103:1502-1510
Kondo, K; Shaim, H; Thompson, P A et al. (2018) Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. Leukemia 32:960-970
Hasan, Md Kamrul; Yu, Jian; Widhopf 2nd, George F et al. (2018) Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia. Blood 132:170-178
Ten Hacken, Elisa; Valentin, Rebecca; Regis, Fara Faye D et al. (2018) Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies. JCI Insight 3:
Gribben, John G (2018) How and when I do allogeneic transplant in CLL. Blood 132:31-39
Sivina, Mariela; Werner, Lillian; Rassenti, Laura et al. (2018) Dynamic changes in CCL3 and CCL4 plasma concentrations in patients with chronic lymphocytic leukaemia managed with observation. Br J Haematol 180:597-600
Ott, Christopher J; Federation, Alexander J; Schwartz, Logan S et al. (2018) Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia. Cancer Cell 34:982-995.e7
Balatti, Veronica; Tomasello, Luisa; Rassenti, Laura Z et al. (2018) miR-125a and miR-34a expression predicts Richter syndrome in chronic lymphocytic leukemia patients. Blood 132:2179-2182

Showing the most recent 10 out of 562 publications