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Holden Comprehensive Cancer Center at The University of Iowa and Mayo Comprehensive Cancer Center
Principal Investigator: George J. Weiner, M.D., The University of Iowa Overall Abstract The University of Iowa / Mayo Clinic Lymphoma SPORE (UI/MC SPORE) consists of 4 research projects, 5 core resources, and the Career Development and Developmental Research Programs. It draws on the complementary strengths 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 immunotherapy, genetics and epidemiology of lymphoma. The interaction of two comprehensive cancer centers on the UI/MC Lymphoma SPORE allows for the performance of translational lymphoma research that would not be possible at each center alone. The overall theme of the SPORE is that Understanding the mechanisms responsible for the anti-tumor activity of anti-lymphoma monoclonal antibody therapy enhances our ability to treat lymphoma using a variety of modalities. The translational nature of the SPORE is highlighted by the inclusion of a clinical trial or population study at the onset in each research project. Current SPORE projects are as follows:
Core resources include
All units within the 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.
Effector cells and anti-lymphoma antibody therapy Monoclonal antibodies (moAbs) are now an accepted component of therapy for non-Hodgkin's lymphoma. Nevertheless, there is still significant uncertainty regarding the relative contributions of the various immune effector mechanisms responsible for the anti-tumor effects of moab. This project was designed to improve our understanding of which effector mechanisms are responsible for anti-tumor effects of moAb therapy and to test the hypothesis that manipulating effector cell function can enhance clinical efficacy. The first aim is to evaluate the immune effector mechanisms responsible for the anti-tumor effects of moAb therapy in a murine model of lymphoma and assess how addition of immunomodulatory CpG ODN impacts on various immune effector mechanisms in that model. Studies in the first aim also involve in vitro evaluation of the effect of novel moAbs, CpG ODN and other agents alone and in combination, on human effector cells and malignant B cells. The second aim involves translation of information gained in aim #1 to the clinic through a series of clinical trials. Successful completion of these studies will give us an excellent understanding of the role of manipulating effector cell function in the setting of moAb therapy and could have a major impact on the immunotherapy of lymphoma and other malignancies as well.
Functional Imaging of Anti-Lymphoma Therapy Despite progress in developing new approaches to therapy of lymphoma, including use of monoclonal antibodies (moAbs), our understanding of the mechanisms responsible for the efficacy of these treatments remains incomplete. Much of what we understand comes from the in vitro analysis of cell lines or lymphoma cells from patients, or evaluation of therapy in murine models. This information has been extremely valuable, however the resulting data often does not reflect what is happening in vivo in patients. In recent years, there has also been significant progress in functional imaging techniques that are allowing us to image biochemical and cellular processes in vivo in patients. A number of functional imaging tools should also be useful in evaluating the cellular and molecular changes that occur in vivo in patients following anti-lymphoma therapy including both moAb therapy and chemotherapy. Three mechanisms of action that are attracting considerable attention are antibody dependent cellular cytotoxicity, apoptosis, and inhibition of proliferation. The current project was designed to help us begin the process of applying in vivo function imaging tools to explore the mechanisms responsible for the anti-lymphoma effects of therapy. In this project, we are evaluating trafficking of radiolabeled mononuclear and polymorphonuclear leukocytes into tumor prior to and after moAb therapy to assess whether binding of moAb to lymphoma cells within nodes leads to a series of events that results in trafficking of effector cells to the involved nodes. We are also determining whether correlation exists between thymidine uptake in tumor using FLT-PET and in vitro assays such as BrdUrd labeling index and % S-phase. These tools could prove extremely valuable as we seek to understand the mechanism of action of a variety of treatments including chemotherapy and moAb therapy, and work to find surrogate markers that will be useful in the design of even more effective approaches to therapy.
Enhancement of Lymphoma Radioimmunotherapy by CpG ODN Immunotherapy with rituximab, an unlabeled monoclonal antibody (MoAb) to CD20, has made a major impact on the treatment of non-Hodgkin lymphoma (NHL); however, most responses are partial and complete remissions (CR) remain elusive. Y2B8 is an anti-CD20 radioimmunoconjugate consisting of a murine MoAb ibritumomab bound to Y-90, a high energy, beta-emitting radioisotope that can routinely be administered as an outpatient. Radioimmunotherapy (RIT) with Y2B8 has produced a higher overall response rate (80%) and a higher CR rate (30%) than unlabled rituximab with excellent patient tolerance. In addition to targeting the tumor cell with unlabeled and radiolabeled antibody, it is our hypothesis that the patient's blood and intratumoral immune effector cells (NK, T-cells, dendritic cells) also should be targeted to improve tumor response and survival. A new class of immunostimulatory agents consisting of oligodeoxynucleotides (ODN) containing the cytosine - guanine (CpG) motif have been shown to upregulate CD20 expression on malignant B-cells and stimulate blood immune effector cells (IECs) to produce cytokines and a Th1 immune response. A phase I trial of CpG ODN in patients with B-cell NHL has demonstrated that CpG ODN can be safely administered in repeated doses to NHL patients without myelosuppression. This project is testing the effects on CpG on the tumor and patient IECs in the context of RIT with Y2B8 through 4 Specific Aims. Aim 1 is a phase I trial that is adding 3 doses of synthetic CpG ODN 7909 to rituximab and Y2B8 in order to develop a new treatment approach for patients with relapsed NHL. Aim 2 is utilizing 111-Indium ibritumomab imaging pre- and post-CpG to test the hypothesis that CpG can indeed upregulate CD20 on tumor cells and enhance Y2B8 tumor:normal organ biodistribution. Aim 3 involves performing translational research studies on blood and tumor samples to learn whether CpG, when given in the context of rituximab and Y2B8, can indeed provide immunostimulation to the IECs. In Aim 4 we are defining the critical genetic and biologic responses to CpG in malignant B cells and benign IECs in indolent and aggressive clinicopathologic types of NHL using fresh tumor samples and gene expression microarrays. In summary, this project is exploring, through a Phase I trial, a new treatment regimen combining CpG with MoAb and RIT. The effects of CpG on malignant lymphoma cells and IECs are being investigated by gene expression arrays and specialized immunoassays on samples from patients participating in the trial to learn how to better exploit the immune system for lymphoma therapy.
Immune and Pharmacogenetic Determinants of Non-Hodgkin Lymphoma Survival For Non-Hodgkin Lymphoma (NHL), a compelling hypothesis is that survival may be related to genetic determinants of host immune status, metabolism or function of therapeutic agents, and DNA repair. We propose to systematically test hypotheses that genes with functional, common variant polymorphisms involved in determining host immune status, metabolism and function of specific therapeutic agents, and DNA repair are associated with overall survival from NHL. Our specific aims are: 1) To evaluate the association of polymorphisms in selected immune-related genes; 2) To evaluate the association of polymorphic genes involved in the glutathione (GSH) synthesis on survival in patients receiving anthracycline-based or alkylating agents, and a polymorphism in the IgG Fc receptor Fc?RIIIa gene (FCGR3A) on survival in patients receiving rituximab; and 3) To evaluate the association of polymorphisms in selected DNA repair pathways in patients receiving alkylating or radiotherapy on survival. We will also evaluate whether any of these effects are independent of other NHL prognostic factors, and treatment modality. To achieve these aims, we are developing a prognostic cohort of all newly diagnosed NHL patients enrolled in the Iowa-Mayo Lymphoma SPORE over a 3-year period (N=1,655) in conjunction with the Clinical Trials and Biospecimens Cores. Treatment and other clinical/laboratory prognostic data are being systematically collected. We are following all patients biannually through the end of the 5-year grant (minimum 2 years follow-up) in order to identify clinical outcomes. Genotyping will be conducted at the Mayo Molecular Epidemiology Core lab. The association of genotype frequencies with NHL survival will be evaluated using standard survival analysis approaches. In summary, in this epidemiology study we will evaluate innovative translational hypotheses regarding the immunogenetic and pharmacogenetic determinants of NHL survival in order to better understand disease pathogenesis, treatment response, and disease prognosis.
Core 1: Administration The University of Iowa/Mayo Clinic Lymphoma SPORE (UI/MC Lymphoma SPORE) Administrative Core stimulates research in lymphoma and expedites the translation of discoveries into new and better methods of prevention, detection, and treatment of lymphoma. The Administrative Core serves as the organizational hub of UI/MC Lymphoma SPORE. It provides an organizational structure designed to efficiently coordinate the activities of the research projects, scientific cores, and developmental programs (Developmental Research Program, Career Development Program) of the SPORE. It also serves to enhance communication between investigators at Iowa and Mayo. The Administrative Core is responsible for coordinating the function of the SPORE committees including the Executive Committee, the Scientific Review Committee and the External Advisory Committee. Dr. George Weiner serves as Director of the Administrative Core, and Drs. Thomas Witzig and Brian Link serve as Co-Directors. These individuals have expertise in laboratory and clinical lymphoma research, as well as extensive administrative experience, and are well qualified to provide leadership and direction for the UI/MC Lymphoma SPORE. The Administrative Core supports SPORE activities by: (1) providing leadership, organizational support, and financial management for UI/MC Lymphoma SPORE investigators; (2) coordinating monthly videoconferences and meetings of UI/MC Lymphoma SPORE investigators, and the ongoing scientific review of SPORE research projects and cores; (3) providing the infrastructure for the selection and support of the best and most promising projects as outlined in SPORE guidelines; (4) providing for information transfer to the scientific community via professional and public means; (5) providing the structure for the establishment and nurture of collaborations to facilitate and expand lymphoma research; and (6) fostering trainee development.
Core 2: Clinical Trials The UI/MC-SPORE Clinical Trials Core (CTC) is a resource available to all SPORE members which has as its primary goal to be the direct translational link between the research projects and clinical research emanating from those projects. In this specific regard the CTC provides dedicated staff to interact with investigators, industry, Institutional Review Boards (IRB), and regulatory agencies to develop clinical trials. They also assist in recruiting patients to trials, schedule protocol tests, assure that translational research imaging and blood and tissue samples are obtained and arrange for data transfer to the Biostatistics Core. The CTC leadership and personnel are responsible for protocol amendments and adverse event reporting. The CTC is integrated within the Clinical Trials Support Cores (CTSC) of the University of Iowa Holden Comprehensive Cancer Center (HCCC) and the Mayo Clinic Comprehensive Cancer Center (MCCC). The Director of the HCCC CTSC, Brian Link, M.D., serves as Director of the UI/MC-SPORE Clinical Trial Core. Joseph Colgan, M.D. of the MCCC Lymphoma Group serves as Co-director. Each cancer center in the SPORE has a well-established protocol review process and clinical trials monitoring plans executed by multidisciplinary (diagnostic, medical and radiation oncologists) personnel that assure the appropriate expertise is available to review potential patient protocols, obtain IRB approval, and to provide periodic review of ongoing protocols to maximize patient safety.
Core 3: Biospecimens The UI/MC Lymphoma Biospecimens Core provides a coordinated, centralized, and dedicated Core for the procurement, processing and annotation of biospecimens from lymphoma patients. The goal of the Biospecimens Core is to procure a variety of biologic specimens on all patients involved in UI/MC Lymphoma SPORE protocols and all newly diagnosed lymphoma patients seen at the University of Iowa Hospitals and Clinics and the Mayo Clinic Rochester. The specific aims of the Biospecimens Core are: 1) to collect, process, distribute, and bank cells from fresh tumor, frozen tumor tissue, paraffin-embedded tumor tissue, serum/plasma, and genomic DNA from lymphoma patients; 2) to track all biospecimens in the UI/MC Biospecimens Database; and 3) to serve as a resource of expertise, collaborative support, and service for projects involving pathology review/classification, immunohistochemistry, in situ hybridization, flourescent in situ hybridization, laser capture microdissection, tissue arrays, and digital image analysis. All specimens will be collected and processed under tight quality control, and will be distributed to UI/MC Lymphoma SPORE researchers or banked for future SPORE research projects. These activities will be tracked using a sophisticated database that merges the activities at Iowa and Mayo, and allows integration with clinical and other data collected in research projects. Over 1000 specimens have been collected to date by the Biospecimens Core.
Core 4: Immunology Many of the research Projects outlined in the UI/MC Lymphoma SPORE, including both preclinical and clinical experiments, require sophisticated correlative immunological studies. Many of these methodologies are complex and require a considerable investment in time, personnel and funds in order to establish in any one laboratory. Moreover, many of these methodologies require rigorous quality controls and, preferably, should employ Good Lab Practice (GLP). Utilizing new methodology and, more importantly, assuring reproducibility and credibility of any given assay is a major burden for any individual laboratory. The Immunology Core was designed to greatly facilitate the adoption and successful execution of new methodology. Ideally, an Immunology Core should be in a Laboratory that practices GLP, which employs extensive quality controls and which has a well defined procedure for troubleshooting each and every assay. These characteristics are the ones examined before the College of American Pathologists (C.A.P.) can certify a laboratory. The Proposed Immunology Core fulfills the above criteria and several of the proposed assays are already approved by C.A.P. The Immunology Core is a resource for the more demanding assays proposed in the UI/MC Lymphoma SPORE. More straight-forward immunologic assays are done in the individual investigators' laboratories. As new approaches are developed, the Immunology Core serves to spearhead the development of these assays even for the experienced investigators. Moreover, if one of the projects finds a need for an immunology assay or procedure, the Core is ready to help the investigators test their modified hypothesis in an efficient, accurate and timely manner.
Core 5: Biostatistics The Biostatistics Core of the UI/MC Lymphoma SPORE provides statistical collaboration and data management support for each of the SPORE projects, the developmental projects, and the Cores. Each of the projects presented in this application reflects input from members of the Biostatistics Core on study design and analysis plan. The Biostatistics Core provides statistical support across many different fields, including epidemiological studies, basic sciences including translational and immunologic correlative studies, gene expression array and imaging, and clinical trials. This comprehensive nature of the Biostatistics Core, which has activities at both the Mayo Clinic and the University of Iowa, assures each SPORE investigator access to statistical expertise that includes collaborative development of study designs and analysis plans, state of the art data analysis and interpretation, data management resources, and abstract and manuscript preparation. The Biostatistics Core also provides a mechanism for the management and integration of both existing and newly collected data through consistent and compatible data handling. Areas of support include database development, data form development and processing, data collection and entry, data archiving, and quality control. This Core complements and assists the efforts of other Cores such as the Clinical Trials, Immunology, and Biospecimens Cores with superior data management and experience with tissue registries. The Biostatistics Core builds upon the innovative and time-tested procedures and systems developed by one of the largest statistical groups in the country whose members have collaborated on more than 8,000 clinical and basic science research studies since 1966. |
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