Lymphoma SPORE Projects
In addition to meeting the fundamental requirements of the National Cancer Institute for translational research projects, the Lymphoma SPORE projects are designed to move the science of lymphoid malignancies forward such that reflect the most innovative ways to generate advances in our understanding of glioma biology and reflect Mayo's strengths in basic, translational, clinical and clinical trials research in gliomas. The investigative teams are interdisciplinary, and include both brain cancer researchers and clinicians who are experienced in patient oriented cancer research. In all cases, the projects are designed so that there is a clear translational trajectory within five years.
Project 1 - A Novel Approach to the Immunotherapy of B Cell Malignancy
Studies supported by the University of Iowa/Mayo Clinic Lymphoma SPORE during the initial funding period demonstrated that immunostimulatory CpG oligonucleotides (ODN) and IL-21 are synergistic in their ability to induce apoptosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) cells. One of the mechanisms responsible for this apoptosis is production of Granzyme B by malignant B cells. Granzyme B production by both CLL cells and other B cell populations is also induced by IL-21 plus anti-B cell receptor antibody (Anti-BCR).
New studies will explore the mechanisms responsible for induction of Granzyme B production by the B cells and how such activity can be utilized therapeutically.
The relative importance of autolysis, undirected cytotoxicity and antibody-directed cellular cytotoxicity in the apoptosis of malignant B cells treated with these agents will be determined. Studies will assess how malignant B cells respond to other combinations of B cell activating agents. In the clinic, correlative studies will be done in conjunction with an ongoing Phase I trial of CpG7909 ODN in CLL to assess whether in vivo therapy with CpG ODN induces changes in CLL cells similar to those observed in vitro.
Studies will be done to evaluate how clinical therapy with CpG ODN impacts on the response of CLL cells to IL-21, and other biological agents in vitro. Additional clinical trials of combinations of biologically active agents in CLL or other B cell malignancies will be tested based on the initial preclinical and clinical results.
Lymphomas are cancers that start in the lymphoid tissues, and includes both Hodgkin lymphoma (otherwise known as Hodgkin disease [HD]), and non-Hodgkin lymphoma (NHL). Treatment advancements for all types of lymphomas over the last several decades have improved the survival of patients with these common malignancies. However, nearly 40 percent of patients with large cell NHL, 80 percent with indolent NHL, and 20 percent with HD are not cured and die of their disease.
Lymphoma cells respond to signals that are transmitted from the outside to the inside of the cell resulting in cell growth. It is clear that new agents with unique mechanisms of action based on knowledge of signal transduction pathways in lymphoma cells are needed to advance lymphoma treatment.
Project 2 of the University of Iowa/Mayo Clinic (UI/MC) Lymphoma SPORE focuses on new drugs for patients with lymphoma that interfere with those signals. Preliminary studies with several of these drugs are promising and the goal of this project will be to combine these agents together and with other common chemotherapy agents to advance the treatment of lymphoma.
The research team is focusing on the phosphatidylinositol-3 kinase (PI3K) and Raf kinase pathways in lymphoma cells. UI/MC Lymphoma SPORE investigators have demonstrated single agent activity in patients with NHL/HD using inhibitors of the PI3K pathway (temsirolimus/everolimus) and inhibitors of farnesyl transferase (tipifarnib). Preliminary in vitro studies demonstrate activity of the Raf kinase/VGFR inhibitor sorafenib against lymphoma cells that is synergistic with the PI3K pathway inhibitors.
Project 3 - Biology and Epidemiology of APRIL and BLyS in B-cell and NHL
There is accumulating evidence that implicate the tumor necrosis factor (TNF) superfamily members BLyS and APRIL, as well as their receptors, as critical factors for the growth and survival of both normal and malignant B cells. BLyS and APRIL are expressed in B-cell non-Hodgkin lymphoma (NHL) and the expression of BLyS is associated with an aggressive disease phenotype.
While it is clear that BLyS expression is required for normal B cell development and homeostasis, the exact source of BLyS in the normal and malignant scenario remains to be fully elucidated. Because serum BLyS levels are elevated in a number of B-cell malignancies known to have a familial incidence, it is possible that dysregulation of BLyS occurs at the genetic level. The environmental, as well as genetic, requirements that mediate BLyS expression remain to be defined, and the promoter for the BLyS gene is poorly characterized.
In preliminary work generated from the University of Iowa/Mayo Clinic (UI/MC) Lymphoma SPORE Developmental Projects, we have found that a polymorphism in the BLyS promoter region correlates with increased serum BLyS levels in patients with B-cell malignancies, particularly those with a family history of B cell-related cancers.
Research in the renewal period will include follow-up on these findings through this new, integrated basic and population science project that utilizes the specimen and epidemiology resources developed through the UI/MC Lymphoma SPORE Biospecimens Core and the Molecular Epidemiology Resource during the last grant cycle (SPORE Project 5). Lymphoma SPORE investigators will determine if genetic variability in BLyS, the BLyS receptors TACI, BCMA, and BAFF-R, as well as the BLyS related TNF molecule APRIL, are associated with the development of NHL and the clinical outcome of patients. In addition to genetic studies, the researchers hope to determine the role of APRIL on the biology of NHL B cells. They hypothesize that APRIL is involved in the growth and survival of malignant B cells and believe that it may contribute to the pathogenesis of NHL.
Identification of patients who have or are predisposed to elevated BLyS and APRIL levels, or those who have genetic alterations in BLyS, APRIL, or their receptors, will provide an opportunity to better understand the significance of these molecules in B-cell malignancies and ultimately to translate these findings to improved clinical management and perhaps novel therapeutic approaches.
Project 4 - Regulatory T-Cells in the Tumor Microenvironment of B-Cell Non-Hodgkin Lymphoma
B-cell non-Hodgkin lymphomas (NHL) are common lymphoid malignancies in which the infiltration of T lymphocytes correlates with the outcome of patients. Despite extensive studies on anti-tumor immunity, the pathophysiological significance of infiltrating T cells in B-cell NHL remains poorly understood. Recent studies have suggested that CD4+CD25+ regulatory T (Treg) cells are involved in the regulation of anti-tumor immunity by inducing peripheral tolerance to tumor specific antigens. However, there are little data regarding the effect of Treg cells on tumor-specific T cell immunity in B-cell NHL and subsequently on the malignant B-cell growth.
In preliminary studies supported by a University of Iowa/Mayo Clinic (UI/MC) Lymphoma SPORE development award, UI/MC team members have identified a subset of CD4+CD25+ T cells with a Treg cell phenotype that are present in B-cell NHL. In addition, the researchers found that these Treg cells have the ability to suppress tumor-infiltrating T cells in B-cell NHL and that they migrate in response to factors such as CCL22 produced by the malignant B cells. Their central hypothesis is that tumor Treg cells contribute to the growth of malignant lymphoma B cells by suppressing tumor-infiltrating T cells and that malignant B cells play an active role by selectively recruiting Treg cells to the areas of B-cell NHL.
In the new grant cycle, the researchers propose to first determine the mechanism by which these Treg cells are recruited to the malignant B-cell microenvironment in non-Hodgkin lymphoma and to discover whether they gain suppressive activity when present in the tumor microenvironment. Second, they will assess whether malignant B cells interact directly with Treg cells in the tumor microenvironment and thereby orchestrate tolerance to their presence. Finally, the investigators plan to establish whether depletion of intratumoral Treg cells, and inhibition of malignant B cells to decrease Treg cell recruitment, will result in clinical benefit for patients with B-cell NHL.
They anticipate that the proposed research will provide a better understanding of the Treg cell-mediated effects in B-cell malignancies. They also anticipate that the clinical use of denileukin diftitox, an interleukin-2 and diphtheria toxin fusion protein, in combination with rituximab, an anti-CD20 monoclonal antibody, will inhibit Treg cells in B-cell lymphoma patients and will also deplete lymphoma B cells in malignant lymph nodes thereby preventing further recruitment of Treg cells into areas of B-cell lymphoma. This treatment combination will lead to a novel therapeutic approach to modulating Treg cells that will result in clinical benefit for patients with B-cell NHL.
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