Chief, Laboratory of Tumor Immunology and Therapeutics, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute, Providence Health & Services
Adjunct Professor of Microbiology and Immunology, School of Medicine, Oregon Health & Science University
Research Interests
The success of current cancer therapies, consisting of surgery, adjuvant radiation and chemotherapy, is mitigated by adverse side-effects and debilitating toxicities associated with their use. In contrast, immunotherapeutic approaches that harness the power of the patient’s own immune system to fight cancer circumvent these adverse effects and have the potential to improve clinical responses and confer protection against cancer recurrence. A major obstacle to the success of cancer immunotherapy is the diminished immune responsiveness of the cancer patient with progressing disease. Several tumor and host-derived factors in the tumor environment are now known to contribute to the failure to mount a substantial anti-tumor immune response. The long-term goal of our laboratory is to better understand the events in the tumor microenvironment that interfere with the immune response and to develop immunologic interventions to overcome them. The strategies we are implementing in the Laboratory of Tumor Immunology and Therapeutics focus on: 1) identifying and neutralizing tumor-generated immunosuppressive products, 2) using novel chemotherapeutic agents to kill tumor cells and provide tumor antigens to activate the immune system and 3) manipulating the immune system to provide long-lasting tumor immunity.
Current Projects
Neutralization of tumor-generated immunosuppressive products: Abundant evidence now exists that implicates an inhospitable tumor microenvironment as a major factor contributing to the lack of substantive anti-tumor effector function in cancer patients. A major project in the laboratory is focused on neutralizing the effects of transforming growth factor beta (TGF-β), an immunosuppressive cytokine that is secreted by many tumor types. To achieve this, we are employing a novel TGF-β receptor kinase inhibitor to block TGF-β signaling. We have found that this small molecule inhibitor effectively prevents TGF-β initiated signaling events, slows tumor progression and reduces the spread of cancer when used in combination with a dendritic cell (DC)-based vaccine. In order to better understand the effects of TGF-β on the immune system and to improve the anti-tumor response against these tumors, we have also developed a transgenic mouse model in which TGF-β signaling is inhibited specifically in DC.
Novel chemotherapeutic agents: Although chemotherapy as a frontline treatment modality of cancer is often effective in controlling tumor growth, it is plagued by undesirable side effects such as toxicity, marrow suppression and generalized immunosuppression. These drawbacks have fueled efforts to identify and test novel anti-cancer agents that are not only capable of destroying existing cancer and preventing recurrent disease but are also minimally toxic to host tissues. A drug with such properties is alpha-tocopheryloxyacetic acid (aTEA) a novel derivative of naturally occurring vitamin E (alpha-tocopherol) that is selectively toxic to tumor cells. Recently, we reported for the first time, that when incorporated into mouse chow and supplied to mice in the diet, aTEA significantly inhibited the growth of a transplanted, highly metastatic breast cancer and dramatically reduced the incidence of spontaneous lung metastases before and after primary tumor establishment without overt toxicity. The stability, relative lack of in vivo toxicity, selectivity for tumor cells and ease of oral delivery, make a-TEA a promising anti-tumor agent with high translational potential. Current efforts are underway to initiate a Phase 1 trial with this agent.
Combinatorial treatment approaches: The Laboratory of Tumor immunology and Therapeutics is also studying the use of dendritic cells (DC)-based vaccines to achieve long-term immune protection against cancer. DC are endowed with the ability to process and present antigens efficiently, secrete a variety of important immunostimulatory cytokines and express critical co-stimulatory molecules necessary for inducing an effective anti-tumor immune response. We have seen that systemic administration of a-TEA in combination with DC vaccination significantly inhibits tumor growth in several mouse models. We have also shown that treatment of tumor cells with a-TEA yields model tumor antigens that are efficiently loaded onto DC for presentation to T lymphocytes. In collaboration with Dr. Hong-Ming Hu of the Laboratory of Cancer Immunobiology at EACRI, we are studying the underlying mechanisms of immune activation by a-TEA. We are also researching the use of a-TEA to enhance immunotherapeutic approaches that are already in the clinic. In collaboration with Dr. Laurence Hurley at the University of Arizona we are examining the efficacy of concurrent anti-HER2/neu antibody (Herceptin) and oral a-TEA treatment against breast cancer. In addition, in a collaborative effort with Dr. Andrew Weinberg of the Laboratory of Basic Immunology at EACRI, we are combining TGF-β inhibition with anti-OX40 therapy to elicit a more durable anti-tumor T cell response.
