The Carson Laboratory
Our Research Aims
- Our research group has worked to elucidate different mechanisms of activation of natural killer cells and their antitumor effects as well as the inhibitory effects of immune suppressor cells on anti-tumor immune cells that are prominent in patients with cancer. We have also investigated the use of targeted anti-cancer drugs in combination with immune-based therapies to treat metastatic melanoma and other cancers, based on the concept that most if not all chemotherapeutic agents have a beneficial effect on the host immune response to cancer. Pre-clinical studies in cell lines and murine models of melanoma have led to NCI-sponsored and industry-sponsored phase I and II translational clinical studies that have garnered NCI peer-reviewed funding.
- Our group also has a long-standing interest in the immune response to interferons and has evaluated downstream signaling pathways in the context of melanoma therapy. We, and others, determined that immune effector cells from patients with advanced cancers exhibit reduced activation of IFN signaling pathways. We discovered that nitric oxide production by immune regulatory cells termed myeloid-derived suppressor cells (MDSC) was the mechanism underlying the reduced immune cell responsiveness to interferons in cancer. We showed that tyrosine kinase inhibitors like sorafenib and ibrutinib could reverse this inhibition. Also, by studying the proteasome, we discovered that proteasome inhibition represents a mechanism to enhance the direct effects of IFN-alpha on melanoma cells thereby complementing its immunostimulatory properties. More recently, we have been investigating the role of microRNAs within melanoma cells in regulating the ability of cancer cells to evade immune detection.
- My laboratory staff and I have evaluated the immune response to monoclonal antibody (mAb) therapy and investigated methods to enhance this response with NK activating cytokines. We have observed that co-administration of IL-12 can potentiate the antitumor actions of an anti-HER2/neu mAb (trastuzumab or HerceptinTM) that is used to treat patients with HER2/neu-expressing breast cancers. This data has served as the basis for NCI-sponsored phase I clinical trials that employ mAbs in combination with IL-12. We continue to investigate how other immune stimulatory agents may be able to augment the immune response to anti-tumor mAbs in other diseases that have a poor prognosis, like pancreatic cancer.
- In collaboration with Barbara Andersen, PhD, we have investigated the effects of behavioral and psychological interventions on the immune function of women with stage II and III breast cancer. We were able to study the effects of stress on the immune system of patients diagnosed with cancer and see that stress can significantly inhibit the host immune response in the setting of cancer. We showed that a tailored psychological intervention reduced stress, improved immunity and improved survival in breast cancer patients. We also discovered that natural killer cell function provides an important “window” into this process. Our goal is to define the mechanisms that underlie the altered immune response of cancer patients and explore ways to reverse this inhibition to enhance the effects of immune-based therapies.
William E. Carson, III