One of the problems faced by CLL patients is that CLL leukemic cells induce a state of immunosuppression that causes increased susceptibility to infections and failure of anti-tumor immune responses. A critical barrier to progress in developing effective immunotherapy is the lack of understanding of molecular mechanisms responsible for the immune dysfunction in CLL. Alterations in levels of certain chemicals in the blood, such as the enzyme IDO, can induce a state of immunosuppression that causes increased susceptibility to infections and failure of anti-tumor immune responses. IDO inhibitors have entered the clinical arena with a promise to restore immune functions in CLL patients. Our central hypothesis is that CLL leukemic cells escape T cell dependent, adaptive immune responses by inducing immune suppressive pathways such as IDO signaling through epigenetic mechanisms. We further hypothesize that IDO blockage will repair the dysfunctional T cells in CLL patients. The objectives of our project are: 1) to determine epigenetic mechanisms of T cell dysfunction in CLL;and 2) to identify biomarkers that are associated with clinical response to an IDO inhibitor, 1-Methyl-D- tryptophan (1-MT), in samples collected from an investigator-initiated, open-label, phase I/II trial of 1-MT in relapsed/refractory CLL patients. We will identify gene expression and epigenetic signatures that are responsible for T cell dysfunction and determine if these biomarkers can predict the improved immune functions in CLL patients treated with 1-MT. The expected outcomes from this study are: 1) improved understanding of epigenetic mechanisms involved in activation of the IDO pathway in leukemia cells and autologous T cells from patients with CLL;and 2) identification of epigenetic biomarkers associated with T cell dysfunction in CLL patients as well as biomarkers that can predict the clinical response of 1-MT in clinical trials. The study will have significant impact on future clinical trials of 1-MT in caner patients. The results will also significantly improve our understanding of the underlying epigenetic mechanisms of tumor-driven immune dysfunction, and will aid the refinement of existing cancer immunotherapy strategies and identify novel targets. Because all cancers are associated with immune deficiency (anergy), and because the biological basis is poorly understood, the outcomes of this study are likely to have a significant broad-spectrum impact on cancer biology and immunology.

Public Health Relevance

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States. Immune dysfunction and the resultant increased incidence of infectious complication accounts for 50 percent of all deaths in patients with CLL. The mechanisms responsible for immune cell dysfunction in CLL remain unclear. Alterations in levels of certain chemicals in the blood, such as the enzyme IDO, can induce a state of immunosuppression that causes increased susceptibility to infections and failure of anti-tumor immune responses. IDO inhibitors have entered the clinical arena with a promise to restore immune functions in CLL patients. The goal of this study is to investigate the molecular mechanism of T cell dysfunction in CLL patients and identify molecular markers that can predict the response of CLL patients to IDO inhibitors in an open-label, phase I/II clinical trial of an ID inhibitor in relapsed/refractory CLL patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA185833-01
Application #
8691290
Study Section
Special Emphasis Panel (ZCA1-RTRB-Z (J1))
Program Officer
Jessup, John M
Project Start
2014-06-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$196,947
Indirect Cost
$66,447
Name
Georgia Regents University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912