My research involves designing and testing novel vaccines against cancer and viral infections in murine and human systems. The major focus of my lab is generating sustained effector and memory T cell immune responses that will translate to therapeutic benefit for cancer patients by developing novel immune modulating strategies to enhance the efficacy of RNA-transfected dendritic cell-based tumor vaccines. CANCER IMMUNOTHERAPY:
The strategies we are using for cancer immunotherapy are based on using antigen presenting cells (APC), specifically dendritic cells (DC), pulsed with tumor proteins or peptides or RNA. This strategy, also described as antigen-specific vaccination, is designed to induce an immune response against a specific antigen that is known to be expressed by the tumor. The dendritic cell-based vaccine approach has become more feasible in humans with technology that allows us to obtain large numbers of dendritic cells from progenitor cells by culturing autologous peripheral blood mononuclear cells in vitro
The ultimate goal of tumor vaccine design is the generation of antigen-specific vaccines. This strategy is obviously based on identification of tumor gene products that are capable of inducing tumor-specific responses. Many cancers do not express a known tumor antigen and vaccination of patients with a broad repertoire of tumor antigens may have several significant advantages over vaccinating with defined tumor antigens. My research has focused on developing a broadly applicable vaccination strategy with tumor-derived antigens that is not dependent on prior knowledge of the tumor antigens expressed in the patients, and is not limited by the availability of tumor tissue from the patient for antigen preparation. We are the key inventors of a groundbreaking technology; using mRNA transfected dendritic cells as vaccines. In a pioneering study, we demonstrated that dendritic cells pulsed with unfractionated total RNA isolated from tumor cells stimulate tumor immunity. We have shown induction of tumor immunity in murine models as well as cytotoxic T lymphocyte (CTL) induction in vitro
in human preclinical studies, using RNA-transfected dendritic cells. We have also developed protocols to amplify the mRNA content from a few tumor cells, thereby generating an unlimited supply of tumor antigen.
The RNA-transfected dendritic cell vaccine platform has been translated to Phase I clinical trials in multiple labs and has established the safety of this approach. UNIVERSAL ANTIGENS:
Vaccinating against tumor-specific antigens for cancer immunotherapy is complicated by the fact that tumor cells are genetically unstable and undergo mutations thereby giving rise to variants that can escape immune detection. We have circumvented this limitation by targeting the antigens expressed in the tumor stroma (e.g. vascular endothelial growth factor). It is widely recognized that tumor progression beyond a minimal size is critically dependent on normal cells known as the tumor stroma. Moreover, since stromal cells, unlike tumor cells, are diploid, genetically stable and exhibit limited proliferative capacity, targeting the stroma could substantially reduce the incidence of immune evasion. Stromal products also provide a source of “universal” antigens that could be targeted in every cancer patient and offer a broad spectrum of candidates from which to choose. REGULATORY T CELLS:
Tumor-induced immune suppression is still a major obstacle in cancer immunotherapy. Our hypothesis is that selective localized modulation of regulatory T (Treg) cell function will enhance the potency of DC-based cancer vaccines. The importance of thymically derived CD4+ regulatory T cells is becoming increasingly evident in many studies that demonstrate the importance of Treg cells in controlling autoimmune manifestations and maintaining