Inflammation, Immunology and Immunotherapeutics

buchsbaum_thumbnail
Donald Buchsbaum, Ph.D.
– Program Co-Leader

weaver_thumbnail
Casey Weaver, M.D.
– Program Co-Leader

Overview:

The objectives of the Inflammation, Immunology, and Immunotherapeutics (III) Program are to build on to and accelerate research in basic immunology and interactions of cancer and the immune system that have led over the past few years to an explosive increase in the successes of immunotherapeutic modalities in cancer.  This will be achieved by developing novel therapeutic approaches for the treatment of leukemia/lymphoma and solid tumors and by understanding and exploiting the basic biology of the immune system’s responses to cancers.

In order to strengthen our research efforts in this area and in response to our External Advisory Committee, we merged most of the previous members in the former Virology Program with the Tumor Immunology Program in 2012 to create the Inflammation, Immunology and Immunotherapeutics Program.  This merger has maximized the synergy between the disciplines of virology and immunology and recognizes the evolving role of inflammation in cancer etiology.

The specific aims of the program are:

  • To investigate the mechanism by which inflammation contributes to the etiology of cancer;
  • To advance basic immunobiology research involving inflammation and T- and B-cell immunology that contributes to understanding of inflammation-immune system tumor interactions to provide novel immunodiagnostics and immunotherapeutics;
  • To identify viral mechanism of immunosuppression and neoplasia;
  • To develop novel approaches for the treatment of cancer utilizing targeted immunotherapy and antibody specificity to deliver apoptotic stimuli, drugs, or radioisotopes to tumors in animal models and humans, and to develop cancer vaccines.

The program is and will study the evolving role of inflammation in cancer, conduct innovative studies into the relationship of inflammatory bowel disease, the microbiome, immune system, and development of cancer.  The program will continue its investigations in regards to HPV vaccines in collaboration with Johns Hopkins University through the joint Cervical Cancer SPORE.

Click here for a complete list of Program Members

Leadership:

Donald J. Buchsbaum, Ph.D., received a Ph.D. degree in Biophysics-Immunology from the University of Rochester in 1972. His mentor was Dr. William F. Bale, a pioneer in the use of radiolabeled antibodies for cancer therapy. Dr. Buchsbaum has been a leading investigator in the field of radioimmunotherapy (RIT) for 35 years. He investigated the use of radiolabeled immunotoxins in experimental lymphoma models. He carried out preclinical localization and therapy studies at the University of Michigan with several B-cell lymphoma monoclonal antibodies labeled with 131I or 90Y. This work included the anti-B1 antibody labeled with 131I, together with unlabeled anti-B1 predosing, which was approved by the Food and Drug Administration (FDA) in 2003 for the treatment of patients with B-cell lymphoma (Bexxar®). He also investigated the treatment of colon cancer xenografts with 90Y-labeled 17-1A and anti-CEA antibodies alone or in combination with chemotherapy. His research also involved comparative dosimetry of external beam irradiation and radioimmunotherapy, and 3D tumor dose distributions for radiolabeled antibodies using serial autoradiography.

At UAB, he has led the preclinical targeted immunotherapy effort with in vitro and animal model studies exploring naked monoclonal antibodies (e.g., Erbitux anti-EGFR and TRA-8 anti-death receptor 5) alone or in combination with chemotherapy or radiation therapy.  The FDA in 2006 approved Erbitux (cetuximab) for use in combination with radiation therapy to treat patients with unresectable squamous cell cancer of the head and neck. This was the first drug approved for head and neck cancer that showed a survival benefit in this population.  Other antibody conjugates were investigated for radioimmunotherapy including a CH2 deleted antibody, pretargeted radioimmunotherapy, immunotoxins, and drug conjugates, including studies of combination therapy with radiation and/or chemotherapy.  He is currently investigating the use of an alpha-emitter conjugated to a B7-H3 antibody for the treatment of pancreatic cancer.  He has also investigated gene therapy strategies for targeting tumor cells using radiolabeled peptides against somatostatin and gastrin-releasing peptide receptors, and molecular prodrug therapy with the cytosine deaminase gene in combination with radiation therapy.  He has investigated the sensitivity of basal breast cancer stem cells to treatment with anti-DR5 antibody in combination with chemotherapy or a Wnt inhibitor. He has also collaborated on genomic studies with HudsonAlpha which identified a novel fusion protein in breast cancer and identified a MHC II prognostic signature in patients with triple negative breast cancer.  He is currently a professor in the Departments of Radiation Oncology, Biochemistry and Molecular Genetics, Pharmacology & Toxicology, Surgery, and Pathology.  He has served on study sections for the NIH, Department of Defense and the Department of Energy.

Casey T. Weaver, M.D., received his M.D. degree (with Honors) from the College of Medicine at the University of Florida in 1984. He received residency training in pathology at Washington University, where he also completed two post-doctoral fellowships in cellular and molecular immunology with Drs. Emil Unanue and Matthew Thomas. After joining the faculty at Washington University, Dr. Weaver was recruited to the University of Alabama at Birmingham, where he is currently the Wyatt and Susan Haskell Professor of Medical Excellence, and a professor in the Departments of Pathology, Medicine and Microbiology.

Dr. Weaver’s research into mechanisms by which developmental decisions of CD4 T lymphocytes control normal and abnormal immune responses has led to new insights into the pathogenesis of autoimmunity and holds promise for new therapies for treating certain autoimmune diseases, as well as cancer and immune- mediated diseases associated with transplantation. Over the past 20 years, the research group led by Dr. Weaver has made fundamental discoveries in the field of immunology that have been the basis for a paradigm shift in our understanding of mechanisms by which T lymphocytes initiate and sustain immune-mediated disease. Whereas it had been thought for more than two decades that there were only two major subtypes of CD4 T cells (Th1 and Th2), which, when dysregulated or ineffectually controlled, could cause tissue damage or immune-mediated disease, it was recently discovered that a third type of CD4 T cell exists (Th17). Findings from Dr. Weaver’s group were central to the identification of Th17 as a major new pathway of immune regulation and have helped to foster the emergence of novel therapies for treatment of immune-mediated diseases. In addition, his group has pioneered methods for defining and tracking the fate of CD4 T cells, which has advanced our understanding of the development of long-lived immune memory. He has developed genomics-based approaches to define how genetic elements control key immune regulatory cytokine genes, and he has defined developmental pathways of regulatory T cells.

A common thread in Dr. Weaver’s past and on-going studies has been modeling of inflammatory bowel disease (IBD), which has provided a focus for understanding the contribution of CD4 T cell development and regulation to chronic inflammatory disease and autoimmunity. This is of special importance with regard to his discoveries related to the Th17 lineage, as this T cell subset now appears to be central to the pathogenesis of most forms of IBD. There is also strong evidence that Th17 cells may play a central role in host protection against certain types of infections, and there is an emerging role for Th17 in anti-tumor immunity.  The Th17 subset was recently reported to uniquely affect the clearance of tumors in a mouse model of melanoma, raising interest in the development and control of this immune pathway for possible therapeutic intervention in certain types of malignancy. Interestingly, however, chronic inflammation driven by the Th17 pathway, such as that found in IBD, has also been linked to the development of malignancy, indicating potential roles for Th17 cells in both the initiation and clearance of certain types of cancer.  Dr. Weaver’s publications have been among the most cited in the immunology literature in the past two decades.

Leadership Activities:

  • Dr. Buchsbaum organized the monthly CCC Tumor Immunology Forum to promote interactions between basic science researchers and translational or clinical science researchers in the Inflammation, Immunology and Immunotherapeutics (III) Program to present their latest work related to diverse aspects of tumor immunology. An important goal of this activity is to strengthen the interactions and increase the interest of the basic immunologists and translational/clinical researchers to develop new collaborative programs together. The Tumor Immunology Forum subsequently was merged with the weekly UAB Program in Immunology Seminar Series, which is organized by a committee on which Dr. Weaver serves. Drs. Buchsbaum and Weaver have alternated in presentations of the III Program at the CCC Strategic Planning Retreats from July 2011 until present. Dr. Weaver founded and heads a bi-weekly T-cell biology meeting with active participation from the research groups of 13 Cancer Center Members (Ballesteros-Tato, Elson, Goepfert, Harrington, Hatton, Hu, Lorenz, Lund, Raman, Randall, Ruiz, Weaver and Zajac).
  • The two co-leaders have complementary experience in basic immunology and translational research. They meet bi-weekly to discuss program development and methods to enhance inter- and intra-programmatic research opportunities.
  • Dr. Buchsbaum is PI of the SPORE in Pancreatic Cancer, a project co-leader in the Breast and Pancreatic SPORE grants, and a member of the Executive Committees of the Breast, Pancreatic, and Brain SPORE grants. He meets regularly with the Cancer Center Director, the Associate Director for Basic Research (Benveniste), and the Associate Director for Clinical Research (Dr. Harry Erba) to discuss the status of the III Program and plans for the future.
  • Dr. Weaver has weekly interactions with members of the III Program via the UAB Program in Immunology Seminar Series. He was co-leader of the Autoimmunity, Immunology and Transplantation (IAT) Steering Committee, which implemented the School of Medicine’s AMC21 strategic plan that shaped organization of the broader UAB Immunology community from 2010 until its transformation into the Inflammation, Immunity and Infection (I3) focus area of the SOM’s revised strategic plan in 2014. Dr. Weaver directs the Gnotobiotic and Genetically Engineered Mouse (GGEM) Facility, which provides breeding capabilities to UAB investigators. The UAB GGEM has provided a basis for a new UAB-CCC Microbiome/Gnotobiotics Shared Facility that is proposed as a new core facility in this competing renewal. In addition, as a Professor in Medicine, Pathology, and Microbiology, he has multiple interactions with a broad range of basic scientists across the campus including scientists and leaders of the Arthritis Center and Center for AIDS Research. He has frequent interactions with the Associate Director of Basic Research, Dr. Etty Benveniste.
  • Drs. Buchsbaum and Weaver also participate in the bimonthly Cancer Center Program Leader’s meeting and annual Program Leader’s Retreat.

Contact Information

Co-Leader: Donald Buchsbaum, Ph.D.
Email: djb@uab.edu
Phone: (205) 934-7077

Co-Leader: Casey Weaver, M.D.
Email: cweaver@uab.edu
Phone: (205) 975-5537

Leave a Reply