Last Updated: 11/29/11
University of Iowa/Mayo Clinic Lymphoma SPORE
George J. Weiner
Director, Holden Comprehensive Cancer Center
University of Iowa
CE Block Chair of Cancer Research
Professor, Dept. of Internal Medicine
Iowa City, Iowa 52242-1002
Tel: 319/353-8620
Fax: 319/353-8988
For more information on this specific SPORE's institution, please visit: http://www.int-med.uiowa.edu/divisions/hemonc/Directory/GeorgeWeiner.html
Overall Abstract
The University of Iowa/Mayo Clinic Lymphoma SPORE (UI/MC SPORE) is a highly successful translational research program that takes advantage of the combined strengths of the translational lymphoma programs of the Holden Comprehensive Cancer Center at the University of Iowa and the Mayo Clinic Comprehensive Cancer Center. Both centers have extensive experience in lymphoma research extending from basic investigation through performance of innovative clinical trials. These two institutions have a long history of collaborating on studies focused on the epidemiology of lymphoma. Scientific accomplishments include translational studies exploring the potential of a novel therapeutic agent, immunostimulatory CpG ODN, as a potential treatment for B cell malignancies, analysis of interactions between lymphoma cells and their microenvironment, and investigation into biomarkers that could have a significant impact on management of lymphoma.
The UI/MC SPORE has supported 7 research projects, 4 core resources, and the Career Development and Developmental Research Programs. Project 5, and parts of project 2, are now being supported by other sources. Projects are as follows:
- A novel approach to the immunotherapy of B cell malignancies
- Signal transduction inhibitor therapy for lymphoma
- Biology and Epidemiology of APRIL and BLyS in B-cell NHL
- Regulatory T-cells in the tumor microenvironment of B-cell non-hodgkin lymphoma
- Immune and Pharmacogenetic Determinants of non-hodgkin Survival
- Target Therapy Exploiting the Malignant B Cell-Microenvironment Interface
- Monoclonal Antibody-Induced NK Cell Activation and Complement
Core resources include Administration, Biostatistics and Bioinformatics, Biospecimens, and Clinical Research that supports both clinical trials and the Molecular Epidemiology Resource of the UI/MC SPORE. All units within the UI/MC SPORE work to draw on the resources of both institutions to expedite the translation of discoveries into new and better approaches to the prevention and treatment of lymphoma.
PROJECT 1: A NOVEL APPROACH TO THE IMMUNOTHERAPY OF B CELL MALIGNANCY
Principal Investigator:
George J. Weiner, M.D. (Iowa)
Co-Principal Investigator:
Clive Zent, M.D. (Mayo)
Co-Investigators:
Zuhair Ballas, M.D.
Brian Link, M.D. (Iowa)
Studies have demonstrated that immunostimulatory CpG ODN and IL-21 are synergistic in their ability to induce apoptosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) cells, and that this apoptosis is independent of benign cells. One of the mechanisms responsible for this apoptosis is production of Granzyme B by the malignant B cells – a surprising finding given that B cells have not previously been shown to produce Granzyme B. It was also found that other B cells can be induced to produce Granzyme B. Further studies demonstrated Granzyme B production by B cells can also be induced by IL-21 plus anti-B cell receptor antibody (Anti-BCR). The identification of a potentially powerful new mechanism of anti-tumor activity opens up a number of new avenues for investigation. This project will continue to explore the mechanisms responsible for induction of Granzyme B production by the B cells, how cells treated in such a manner mediate anti-tumor activity, and how such activity can be utilized therapeutically. These studies, which will make extensive use of all of the UI/MC SPORE shared resources, will provide valuable information on how the unexpected immunologic finding that B cells can produce functional Granzyme B, can be applied to the treatment of Lymphoma and other B cell malignancies.
The two specific aims of this project are:
Aim 1: Assess the effects of IL-21, CpG ODN, and other B cell activators, on malignant B cells in vitro.
Aim 2: Perform early phase clinical trials of biological therapy in subjects with CLL and assess the impact of treatment on the biology of CLL cells.
PROJECT 2: SIGNAL TRANSDUCTION INHIBITOR THERAPY FOR LYMPHOMA
Principal Investigator:
Thomas Witzig, M.D. (Mayo)
Co-Principal Investigator:
Scott Kaufmann, M.D., Ph.D. (Mayo)
Co-Investigators:
Raymond Hohl, M.D., Ph.D. (Iowa)
Patrick Johnston, M.D., Ph.D.
Shaji Kumar, M.D., (Mayo)
Lymphomas are the fifth most common neoplasms in the United States, with nearly 80,000 new cases of non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) each year. Treatment advances over the last several decades have improved the survival of patients with these common malignancies. However, nearly 40% of patients with large cell NHL, 80% with indolent NHL, and 20% with HD are not cured and die of their disease. New agents with unique mechanisms of action based on knowledge of signal transduction pathways in lymphoma cells are needed to advance lymphoma treatment. This project will focus on the phosphatidylinositol-3 kinase (P13K) and Raf kinase pathways in lymphoma cells. The overall hypothesis is that a combination of chemotherapy agents with one or more of the signal transduction inhibitors (STIs) will improve the response rate and survival of patients with NHL/HD. To test this hypothesis, we will include clinical trials that assess rational combinations of STIs with each other and with conventional chemotherapy agents, investigational biomarkers in lymphoma cells from patients participating in these trials, and in vitro studies of new agents and combinations in primary tumor cells that will lead to the next generation of clinical trials including study of combinations with substantial clinical activity in the cooperative groups. Project 2 is also partially funded by an R01 (CA127433-01).
This work is organized in 3 specific aims:
Aim 1: To investigate the safety and efficacy of PI3K/Akt/mTOR pathway inhibitors in combination with Raf-kinase inhibitors and conventional chemotherapy agents.
Aim 2: To assess the action of combinations of STIs on the targeted pathways and identify potential markers of anti-tumor efficacy using malignant B-cells from patients entered on the trials in Aim 1.
Aim 3: To investigate novel combinations containing agents targeting the PI3K/Akt/mTOR pathway and other STIs or conventional agents in malignant B-cells in vitro to provide the rationale for the next generation of clinical trials.
PROJECT 3: BIOLOGY AND EPIDEMIOLOGY OF APRIL AND BLYS IN B-CELL AND NHL
Co-Principal Investigators:
James R. Cerhan, M.D., Ph.D.
Anne Novak, Ph.D. (Mayo)
Co-Investigators:
Gail Bishop, Ph.D., and
Brian Link, M.D., (Iowa)
Stephen Ansell, M.D., Ph.D., and
Richard Bram, M.D., Ph.D., (Mayo)
There is accumulating evidence that implicate the 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, which is better characterized than APRIL, has been found to be elevated in a number of immune disease models and there is increasing evidence that it may correlate with pathogenesis of various B cell related disorders, including B cell malignancies. 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 our 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. We now propose to follow-up these findings through a 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 first project period. We 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 our genetic studies we also propose to determine the role of APRIL on the biology of NHL B cells. We hypothesize that APRIL is involved in the growth and survival of malignant B cells and 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 us with 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. To address these questions we propose the following aims:
Aim 1. To evaluate the association of inherited variability in genes encoding BLyS, APRIL, and their key receptors, with risk of NHL.
Aim 2. To evaluate the association of inherited variability in genes encoding BLyS, APRIL, and their key receptors, with NHL survival.
Aim 3. To functionally characterize the BLyS promoter polymorphisms and identify inflammatory mediators involved in BLyS expression.
Aim 4. To determine the significance of APRIL and its receptors in the survival and proliferation of NHL B cells.
PROJECT 4: REGULATORY T-CELLS IN THE TUMOR MICROENVIRONMENT OF B-CELL NON-HODGKIN LYMPHOMA
Principal Investigator:
James R. Cerhan, M.D., Ph.D. (Mayo)
Co-Investigators:
Thomas M. Habermann, M.D. (Mayo)
Brian Link, M.D. (Iowa)
B-cell non-Hodgkin lymphomas (NHL) are common lymphoid cancers in which malignant cells arrested at various stages of differentiation proliferate within lymph nodes and occasionally other tissues. However, cells other than tumor cells are commonly present in the tumor microenvironment. These cells include T lymphocytes that seem to be more than simple residual elements from the normal lymph node structure. It is commonly believed that these infiltrating immune cells are targeting the cancer cells, yet they appear unable to eradicate the malignant cells. Despite extensive studies regarding anti-tumor immunity, the significance of infiltrating T cells in B-cell NHL remains poorly understood.
Recent studies in other cancers have suggested that regulatory T (Treg) cells are involved in the control of anti-tumor immunity by inducing tolerance to the tumor. It has been shown that Treg cells influence tumor immune responses by suppressing tumor-specific immune cells. 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. Studies in B-cell lymphoma have described a T-cell or immune signature in the tumor that correlates with patient outcome. The immune infiltrate is usually comprised of CD4+ and CD8+ T-cells as well as monocytes.
Our hypothesis is that intratumoral Treg cells in patients with B-cell NHL significantly upregulate their ability to suppress tumor specific T-cell responses as they enter sites infiltrated by malignant B-cells. We further postulate that malignant B-cells play an active role in this process by direct activation of Treg cells thereby facilitating immune tolerance to their presence.
To determine whether localization of Treg cells influences their suppressive capacity and to define the role of malignant B-cells in the migration and activation of Treg cells in patients with B-cell lymphoma, we propose the following aims:
Aim 1: To show that Treg cells are pathologically recruited to areas of B-cell NHL and gain suppressive function when present in the malignant lymph nodes.
Aim 2: To determine whether malignant B-cells directly interact with Treg cells to facilitate immune tolerance.
Aim 3: To test whether therapeutic inhibition of Treg cell recruitment and function results in significant clinical benefit for patients with B-cell NHL
PROJECT 5: REGULATORY T-CELLS IN THE TUMOR MICROENVIRONMENT OF B-CELL NON-HODGKIN LYMPHOMA
Principal Investigator:
Stephen Ansell, M.D., Ph.D. (Mayo)
Co-Investigators:
Brian Link, M.D., (Iowa)
Richard Bram, M.D., Ph.D., and
Keith Knutson, Ph.D. (Mayo)
The aims identified in the original application were:
Aim 1: To evaluate the association of polymorphisms in selected immune-related genes from four key pathways (inflammatory and regulatory cytokines, Th1/Th2, innate immunity, and chemokines) on overall NHL survival.
Aim 2: To evaluate the association of polymorphic genes in selected pathways critical to the metabolism and function of specific therapeutic agents on overall NHL survival. Specifically, glutathione (GSH) synthesis in patients receiving anthracycline-based or alkylating agents and IgG Fc receptor Fc?RIIIa gene in patients receiving rituximab.
Aim 3: To evaluate the association of polymorphisms in selected DNA repair pathways (base excision, nucleotide excision, homologous recombination) in patients receiving alkylating therapy and/or radiation on overall NHL survival.
Over 2,500 patients enrolled in this study. This project represented a highly interdisciplinary collaboration in epidemiology/population science, clinical medicine, and pharmacogenomics.
PROJECT 6: TARGET THERAPY EXPLOITING THE MALIGNANT B CELL-MICROENVIRONMENT INTERFACE
Principal Investigator:
Grzegorz Nowakowski, M.D. (Mayo)
Co-Investigators:
Diane Jelinek, Ph.D.
Neil Kay, M.D.
Thomas Witzig, M.D. (Mayo)
Significant advances have been made in the treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) in the last several decades. However, despite high response rates to initial therapy, a significant portion of patients with NHL and virtually all patients with CLL will relapse and eventually develop a drug resistant form of their disease. In this regard, intercellular interactions of the malignant B cell with the microenvironment are known to play a key role in promoting tumor cell survival after exposure to cytotoxic therapy. This phenomenon is known as cell adhesion mediated drug resistance (CAM-DR). VLA-4 (very late antigen 4, ?4?1 integrin) is a well studied adhesion receptor known to play a crucial role in tumor cell adhesion, homing and CAM-DR. VLA-4 it is constitutively expressed on the tumor cells of B cell malignancies. Tumor cells from patients with chemotherapy-resistant lymphoma over-express VLA-4 and the adhesion of lymphoma and CLL cells to the bone marrow stroma through VLA-4 mediates drug resistance. Conversely, disruption of VLA-4 mediated adhesion results in reversion to a drug sensitive phenotype.
We hypothesize that strategies that target and block VLA-4 will be of significant value in treating human NHL and CLL by overcoming CAM-DR. We therefore propose to i) determine the impact of VLA-4 blocking on CAM-DR for a broad spectrum of anti-lymphoma agents in cell adhesion systems in vitro; ii) determine the impact of VLA-4 blocking on tumor cell mobilization to peripheral blood and on CAM-DR in vivo iii) determine the clinical benefit of VLA-4 targeting therapy in NHL and CLL. Our preliminary data indicates that the effect of VLA-4 blockage on overcoming CAM-DR may be drug specific. In this regard, we anticipate that preclinical studies will identify agents and combinations showing synergy with VLA-4 blockage. These agents will be then selected based on clinical feasibility and synergy data for testing in clinical trial(s) in combination with VLA-4 blockage.
Tumor cells depend on the support of other cell types in the body for survival and growth. Also, a failure of cancer treatment is often related to the support that other cells in the body give to the tumor. Eliminating this support is critical for successful cancer therapy. This proposal focuses on the ways in which this support can be eliminated to improve treatment of lymphoma and chronic lymphocytic leukemia
Three aims are proposed:
Aim 1: Investigate the ability of natalizumab to induce significant levels of apoptosis in malignant B cells and to overcome cell adhesion mediated drug resistance (CAM-DR) as measured using in vitro model systems.
Aim 2: Evaluate the ability of natalizumab to mobilize malignant B cells to circulation and to inhibit CAM-DR in vivo.
Aim 3: Develop a phase I/II clinical trial of natalizumab in B cell malignancies.
PROJECT 7: MONOCLONAL ANTIBODY-INDUCED NK CELL ACTIVATION AND COMPLEMENT
Principal Investigator:
Emil Racila, M.D. (Iowa)
Co-Principal Investigator:
George Weiner, M.D. (Iowa)
Co-Investigators:
Clive S. Zent, M.D. (Mayo)
Despite the certain clinical value of anti-B-cell monoclonal antibody (mAb) therapy, there is much to learn about the mechanisms responsible for its anti-tumor activity and how these mechanisms interact. NK-cell mediated antibody-dependent cellular cytotoxicity (ADCC) and complement fixation both appear to play a role. Recent in vitro data demonstrates serum complement blocks activation of NK cells by rituximab-coated target B-cells. More specifically, C3b blocks interaction between mAb Fc and CD16. Additional studies demonstrated target cells coated with low levels of rituximab activate NK cells but do not fix complement, while target cells coated with high levels of rituximab fix complement but do not activate NK cells. Since complement fixation does not always lead to complement-mediated lysis, these studies suggest complement fixation could limit mAb efficacy. The current studies were designed to explore these findings further with a focus on their clinical implications. Specific aim #1 will explore in vitro the relationship between complement fixation and NK activation induced by mAb-coated target cells and will include studies evaluating whether alemtuzumab has effects similar to those observed with rituximab. The impact of complement fixation on NK activation within involved lymph nodes and tissues will be studied using a system designed to mimic complement that is present in the extravascular space. Specific aim #2 will assess the effect of mAb on complement activation and NK activation in the clinic using samples obtained from subjects enrolled on two clinical trials. The first will include subjects with Chronic Lymphocytic Leukemia treated with low dose rituximab and alemtuzumab. The second will include lymphoma subjects receiving standard dose rituximab, and will involve assessing the state of NK and complement activation at the time of infusion reactions that are common during the first treatment with rituximab. The hypothesis for this aim is that there is a window of rituximab concentrations that activates NK cells but does not fix complement, and that the concentrations of rituximab present after lower dose therapy or at the time of infusion reactions fall within this window.
These studies will take place at both Iowa and Mayo, are highly translational, and will take advantage of the resources available through the SPORE. Results from these studies will provide important information related to the relationship between mAb levels, NK activation and complement that is clinically relevant and could lead to the design of more effective mAb-based treatment regimens.
Aim 1: Explore in vitro the relationship between complement and NK activation by rituximab and alemtuzumab-coated target cells.
Aim 2: Evaluate the effect of rituximab and alemtuzumab serum concentration on complement activation, NK activation and ADCC in patient samples.
- Specific Aim 2A: Samples obtained at select time points from patients enrolled on a clinical trial of low dose mAb therapy of CLL.
- Specific aim 2B: Samples obtained before, during and after infusion reactions in lymphoma subjects receiving standard dose rituximab therapy.
- Samples will be obtained at key time-points from patients receiving therapy in a clinical trial involving initial treatment with low dose rituximab and subcutaneous alemtuzumab. MAb levels, NK activation, cytokine levels and complement status will be determined and compared. In addition, we will evaluate cytokine release and NK activation in specimens collected before, during the infusion reaction and at the completion of rituximab infusion in lymphoma patients receiving standard dose rituximab therapy.
CORE 1: ADMINISTRATION
Director:
George J. Weiner, M.D. (Iowa)
Co-Director:
Thomas Witzig, M.D. (Mayo)
The overall goal of the University of Iowa/Mayo Clinic Lymphoma SPORE (UI/MC SPORE) Administration Core is to stimulate research in lymphoma and to expedite the translation of discoveries into new and better methods of prevention, detection, and treatment of lymphoma.
CORE 2: BIOSPECIMENS
Director:
Ahmet Dogan, M.D., Ph.D. (Mayo)
Co-Director:
Sergei Syrbu, M.D., Ph.D. (Iowa)
The UI/MC SPORE Biospecimens Core provides a coordinated, centralized, and dedicated Core for the procurement, processing and annotation of biospecimens from lymphoma patients and patients with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). The goal of the Biospecimens Core is to procure a variety of biologic specimens on all patients involved in UI/MC SPORE protocols and all newly diagnosed lymphoma patients seen at the University of Iowa and the Mayo Clinic Rochester.
Core 3: Biostatistics and Bioinformatics
Director:
Susan M. Geyer, M.D., (Mayo)
Co-Director:
Terry Braun, Ph.D.
Brian Smith, Ph.D. (Iowa)
The Biostatistics and Bioinformatics Core (BABC) provides statistical collaboration and data management support for each of the SPORE projects, the developmental projects, and the other Cores. In addition, the BABC also provides collaboration and support in bioinformatics and computational biology research for SPORE projects as appropriate.
CORE 4: CLINICAL RESEARCH
Co-Director:
Brian Link, M.D. (Iowa)
Thomas Habermann, M.D. (Mayo)
Co-Investigator:
Patrick Johnston, M.D., Ph.D. (Mayo)
The UI/MC SPORE Clinical Research Core (CRC) has as its primary goal to be the direct translational link between research projects and clinical research emanating from these projects. The CRC coordinates the development of clinical trials, assists in patient accrual, manages and reports adverse events to appropriate agencies, and provides quality control on clinical trial data. The CRC also hosts the Molecular Epidemiology Resource. The CRC provides a critical link between clinical research and the specific projects and cores.
