Carson, William
William E. Carson, M.D.
Assistant Professor
Department of Surgery
Joint Appointment
Department of Molecular Virology, Immunology and Medical Genetics
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Research Program:
Our laboratory is interested in the interactions that occur between the immune system and patient tumors. Our research addresses the mechanism of action of cytokine therapy in the setting of malignancy. We have three ongoing projects that began as basic in vitro observations that have now been translated into the clinical setting. One major area of research involves the use of cytokines to enhance the actions of interferon-alpha (IFN-a). This cytokine has activity in the setting of metastatic disease as well as in the adjuvant setting following surgery for high-risk lesions (tumors > than 4 mm or lymph node involvement). We have found that pre-treatments of interleukin-12 (IL-12) can sensitize tumor cells to the actions of low-dose IFN-a, thereby allowing lower, less toxic doses to be administered. This work has been translated into phase II trial at the national level. Our current efforts center on an analysis of the host immune response to this treatment at the level of cytokine signal transduction and ways to optimize dosing of cytokines on an individual basis.
A second area of research in our laboratory involves the use of cytokines to enhance the actions of anti-tumor monoclonal antibodies (mAb). We observed that co-administration of IL-12 can potentiate the anti-tumor actions of an anti-HER2/neu mAb (Herceptin) that is used to treat patients with HER2/neu-expressing breast cancers. This data has served as the basis for a NCI-sponsored phase I clinical trial which employs Herceptin in combination with IL-12. Current laboratory efforts are aimed at understanding the mechanism underlying the synergy of these two treatments as well as the analysis of immune cells obtained from patients enrolled in this type of trial. A follow-up trial of IL-12 and Herceptin in combination with chemotherapy (paclitaxel) has just finished accrual. This trial represents the very first clinical use of a cytokine, a mAb, and a chemotherapeutic agent in combination. We are currently investigating the ability of other immunomodulatory agents to enhance the effects of therapeutic monoclonal antibodies.
A third area of interest is the effects of stress on the immune system of patients diagnosed with cancer. We hypothesize that stress can significantly inhibit the host immune response in the setting of breast cancer and have discovered that natural killer cell function provides an important "window" on this process. We are currently collaborating with Professor Barbara Andersen of the Dept. of Psychology who is investigating the effects of behavioral and psychological interventions on the immune function of women with Stage II and III breast cancer via a randomized clinical trial. We hypothesize that these interventions will result in reduced stress, which in turn will lead to improved immune function and lowered cancer recurrence rates. We are currently developing a series of novel functional tests of immune competence which are applicable to patients receiving anti-cancer therapy.
Research Resources:
Our laboratory is located in Room 380 of the Medical Research Facility of the Ohio State University. The following major equipment is available tomembers of Dr. Carson’s lab: 2 laminar flow hoods, 1 chemical hood, 1 C02 incubator, 1 table-top centrifuge, 2 micro-centrifuges, 1 hybridization oven, scintillation counter, gamma counter, PCR thermocycler, BioAssay Reader (Perkin Elmer), cell harvester, -80°C freezer, -20°C freezer, 1 standard refrigerator, 1 liquid Nitrogen freezer, bacterial shaker, standard and inverted microscopes, Eagle Eye gel imaging system, and basic gel electrophoresis equipment. A Perkin-Elmer Taqman 7700 Sequence Detector for Real Time RT-PCR is located in Rm 350 of the MRF and serves as a core facility for the Comprehensive Cancer Center. It is available for Dr. Carson’s unrestricted use.
Selected Publications:
Carson WE, Shapiro C, Crespin TR, Thornton LM, Andersen BL. Cellular immunity in breast cancer patients completing taxane treatment. Cellular immunity in breast cancer patients completing taxane treatment. Clin Cancer Res, 10:3401-9, 2004.
Andersen B, Golden-Kreutz D, Emery C, Crespin T, Shapiro C, Farrar W, Carson WE. Psychological, behavioral, compliance & immune changes following a psychological intervention: A clinical trial. J Clin Oncol, 22:3570-80, 2004.
Parihar R, Nadella P, Lewis A, Jensen R, DeHoff C, VanBuskirk AM, Magro CM, Shapiro CL, Carson WE. A Phase I Study of Interleukin-12 with trastuzumab in patients with HER2-overexpressing malignancies: Correlation between response and sustained interferon-gamma production. Clin CA Res, 10:5027-37, 2004.
Lesinski GB, Badgwell B, Hu Y, JZimmerer J, Abood G, Carson WE. Interleukin-12 pre-treatments enhance interferon-alpha-induced Jak-STAT signaling and potentiate the anti-tumor effects of interferon-alpha in a murine model of malignant melanoma. J Immunol, 172:7368-76, 2004.
Lesinski, GB, Kondadasula SV, Crespin T, Kendra K, Walker M, Carson WE. Multiparametric flow cytometric analysis of interpatient variation in STAT1 phosphorylation following IFN-alpha immunotherapy reveals dose-dependent signal transduction. J Natl Cancer Instit, 96:1331-42, 2004.
Lesinski GB, Valentino D, Hade EM, Jones S, Magro C, Chaudhury AR, Walker MJ, Carson WE. Expression of STAT1 and STAT2 in malignant melanoma does not correlate with response to interferon-alpha adjuvant therapy. Cancer Immunol. Immunother. 54:815-25, 2005.
Trotta R, Parihar R, Yu J, Becknell B, Allard J 2nd, Wen J, Ding W, Mao H, Tridandapani S, Carson WE, Caligiuri MA. Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation. Blood. 105:3011-8, 2005.
Lesinski GB, Sharma S, Varker KA, Sinha P, Ferrari M, Carson WE. Release of biologically functional interferon-alpha from a nanochannel delivery system. Biomedical Microdevices. 7:71-9, 2005.
Roda J, Parihar R, Carson WE. CpG-containing oligodeoxynucleotides act through toll-like receptor 9 to enhance the natural killer cell cytokine response to antibody-coated tumor cells. J. Immunol. 175:1615-27, 2005.
Parihar R, Trotta R, Roda JM, Tridandapani S, Caligiuri MA, Carson WE. The inositol 5’ phosphatase SHIP-1 negatively regulates the NK cell response to antibody-coated target cells and IL-12. Cancer Research, In Press, 2005.
Roda JM, Parihar R, Magro C, Nuovo G, Tridandapani S, Carson WE. NK cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Cancer Research, In Press, 2005.
Lesinski GB, Eisenbeis CF, Anghelina M, Parihar R, Valentino D, P. Nadella P, Sundaram M, Sznol M, Walker MJ, Carson WE. A phase I study of the sequential combination of interleukin-12 and interferon-a2b: Evidence for modulation of interferon signaling pathways by interleukin-12. J. Clin. Oncol. In Press, 2005.
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