PROJECT 4 : Immune Tolerance and Stem Cell Transplantation Impaired immune responses are common in cancer and a particular feature of chronic lymphocyfic leukemia (CLL). The immune dyfuction in CLL is characterised by hypogammaglobulinemia and autoimmune phenomena and infecfious complicafions are a major cause of morbidity and mortality in this disease. Previous work in this Program has demonstrated a direct effect of CLL cells on T cells, both in human samples and in the Eji-TCL1 transgenic mouse model of this disease, that result in changes in acfin polymerizafion in T and NK cells and failure ofthese cells to mount effecfive immune synapses with antigen presenting cells. The central hypothesis of this project Is that specific T cell defects result from interaction of CLL cells with the patient's immune system and that repair of these defects will be required to maximize T cell mediated immune responses in vivo. We therefore seek to characterize the basis for defective immune cell function in CLL and repair these defects for future therapeutic intervenfion. We shall examine this in human samples from pafients with CLL and in an E(i-TCL1 transgenic mouse model of this disease. Since most agents that are used to treat CLL also add to the immune suppression, the project will determine whether novel agents in clinical trials in this Program have impact on the host immune system and are therefore likely to worsen immune funcfion. Work will also be performed to assess the nature of T cell mediated anfi-tumor immune responses against CLL cells and to determine if these specific T cell responses occur following allogeneic stem cell transplantafion for CLL. The goal here is to characterize the nature ofthe graft versus leukemia effect in CLL. To address these issues this project will address the following specific aims: First, to define the molecular mechanism whereby molecules expressed by CLL cells induce dysfunction in T and NK cell in patients with CLL and the role of immunomodulatory drug intervenfion to repair these defects. The goal here is to improve immune funcfion in CLL pafients. Second, to assess the impact of in prevention of induction of T cell defects vivo in the Emu-TCLI transgenic mouse model of CLL and asses its impact on diease progression. Third, to characterize targets of graft versus leukemia effect in CLL after allogeneic stem cell transplantafion in CTN/ CALGB 100701. Taken together, these studies will assess the impact of immune mediated responses in CLL.

Public Health Relevance

This project has demonstrated that CLL cells induce defects in the host immune. In keeping with our original hypothesis that CLL would act as a model disease, based on this knowledge, we have demonstrated similar defects in acfin polymerization in T cells in pafients with other hematologic malignancies including acute myeloid leukemia, follicular lymphoma, diffuse large cell lymphoma, myeloma, breast, ovarian and pancreatic cancer. Findings from this project therefore have broad implications in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA081534-12A1
Application #
8235343
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (O1))
Project Start
2011-12-01
Project End
2017-08-31
Budget Start
2012-09-24
Budget End
2013-08-31
Support Year
12
Fiscal Year
2012
Total Cost
$253,601
Indirect Cost
$42,487
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kashyap, Manoj K; Kumar, Deepak; Jones, Harrison et al. (2016) Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway. Oncotarget 7:2809-22
Lamothe, Betty; Wierda, William G; Keating, Michael J et al. (2016) Carfilzomib Triggers Cell Death in Chronic Lymphocytic Leukemia by Inducing Proapoptotic and Endoplasmic Reticulum Stress Responses. Clin Cancer Res 22:4712-26
Oakes, Christopher C; Seifert, Marc; Assenov, Yassen et al. (2016) DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet 48:253-64
Balatti, Veronica; Acunzo, Mario; Pekarky, Yuri et al. (2016) Novel mechanisms of regulation of miRNAs in CLL. Trends Cancer 2:134-143
Lampson, Benjamin L; Kasar, Siddha N; Matos, Tiago R et al. (2016) Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood 128:195-203
Salzer, Elisabeth; Cagdas, Deniz; Hons, Miroslav et al. (2016) RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nat Immunol 17:1352-1360
Dhar, Sachin; La Clair, James J; León, Brian et al. (2016) A Carbohydrate-Derived Splice Modulator. J Am Chem Soc 138:5063-8
Hawkins, Edwin D; Duarte, Delfim; Akinduro, Olufolake et al. (2016) T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. Nature 538:518-522
Sarkar, Aloke; Balakrishnan, Kumudha; Chen, Jefferson et al. (2016) Molecular evidence of Zn chelation of the procaspase activating compound B-PAC-1 in B cell lymphoma. Oncotarget 7:3461-76
Thompson, Philip A; O'Brien, Susan M; Xiao, Lianchun et al. (2016) β2 -microglobulin normalization within 6 months of ibrutinib-based treatment is associated with superior progression-free survival in patients with chronic lymphocytic leukemia. Cancer 122:565-73

Showing the most recent 10 out of 440 publications