 |
|
||
 |
|||
       |
|||
|
|||||||||
|
|
 |
William E. Carson III
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-alpha). 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-alpha , thereby allowing lower, less toxic doses to be administered. This work has been translated into a CALGB cooperative group phase II national trial. Our current efforts center on an analysis of the host immune response to this treatment at the level of cytokine signal transduction. Recently, we have developed flow cytometric techniques that permit us to monitor the activation of specific signaling pathways within individual immune subsets in patients that have received cytokine therapy (IFN-alpha or IL-2). Our ultimate goal is to use this technique to identify optimal doses of cytokine for individual patients. We have also characterized the inhibitory effects of SOCS (suppressors of cytokine signaling) proteins on IFN-alpha-induced cytokine signaling. These experiments have shown that removal of inhibitory signals can markedly enhance the anti-tumor effects of cytokine therapy. Finally, we are investigating the ability of novel targeted agents such as proteasome inhibitors and anti-angiogenic agents to augment the immune stimulatory effects of cytokine therapies. This work has been translated into a clinical trial of a proteasome inhibitor (bortezomib) plus IFN-alpha and an NCI-sponsored trial of an anti-VEGF antibody (bevacizumab) and IFN-alpha. 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 (trastuzumab or 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 trastuzumab in combination with IL-12 and a follow-up trial of IL-12 and trastuzumab in combination with chemotherapy (paclitaxel). This trial represents the very first clinical use of a cytokine, a mAb, and a chemotherapeutic agent in combination. Importantly, patients who experienced clinical benefit in response to IL-12 and trastuzumab also exhibited production of IFN-gamma by activated NK cells. Patients with progressive disease did not show any evidence of immune activation. We are currently investigating the genetic factors that influence the patient response to mAb/cytokine combinations. Recent work from our group indicates that other immune stimulatory agents may be able to augment the immune response to anti-tumor mAbs. Agents that are currently under investigation include toll-like receptor agonists and novel cytokines such as IL-21. Education & Training 1978-79 Research Asst., Department of Medicine, Univ. of California, Irvine Medical Center, Orange, CA. 1980-81 Research Asst., Department of Biochemistry, 1986-91 Intern and Resident in Surgery, 1988-89 Postgraduate Research Surgeon, Department of Immunology, 1991-93 Clinical Fellow in Surgical Oncology, Roswell Park Cancer Institute, 1991-94 Clinical 1993-95 Research Fellow in Surgical Oncology, Departments of Surgery and Molecular Medicine, Roswell Park Cancer Institute, |
|
|
|
William E. Carson III, MD
