Geoffrey Stone, Ph.D.
Assistant Professor of Microbiology & Immunology
Description of Research
A fundamental challenge in modern immunology is the development of effective and safe vaccines. The main focus of Dr. Stone's laboratory is vaccine adjuvant development. Vaccines are developed both to prevent an initial infection (prophylactic vaccination) as well as enhancing the immune response in cancer patients (therapeutic vaccination). Dr. Stone's laboratory utilizes basic research in molecular biology, protein biochemistry, immunology, and viral pathology to develop innovative approaches to HIV vaccine development, including novel molecular adjuvants. In addition, Dr. Stone is interested in the application of these new adjuvant technologies to related vaccines against cancer, malaria, and other infectious diseases. By developing a 'Bench to Bedside' approach to vaccinology, novel ideas from basic immunology research are tested at the University of Miami in collaboration with partners in GMP manufacture and clinical trial development.
Clinical Studies of therapeutic HIV vaccines utilizing ex vivo antigen-loaded dendritic cells: HIV infected patients display a strong cellular immune response to the virus, but this response is unable to effectively control viral load and maintain CD4+ T cell counts in the majority of individuals. Dr. Stone's laboratory is exploring the use of mRNA transfected dendritic cells as a method to enhance CD4+ and CD8+ T cell responses in these patients, potentially leading to long term control of viremia and maintanence of CD4+ T cells. This research follows the successful induction of anti-tumor immune responses in cancer patients treated with mRNA-transfected autologous dendritic cells in Phase I clinical studies. This highly efficient vaccination protocol is able to induce potent CD4+ and CD8+ T cell responses against tumor antigens that were previously ignored in the immune system. Similarly, in HIV vaccination the loading of monocyte derived dendritic cells with HIV antigen mRNA leads to an upregulation of IL-2 and Interferon gamma secretion by host T cells in vitro. In collaboration with Dr. Eli Gilboa, Dr. Stone's laboratory has begun pre-clinical work using HIV-positive patient samples to study T cell responses after ex vivo loading of dendritic cells with mRNA encoding HIV-1 antigens, in preperation for a clinical trial of HIV therapeutic vaccines. These studies explore the optimal formulation of antigen mRNA, mRNA transfection method, molecular adjuvants, and dendritic cell maturation process which is likely to induce a T cell phenotype strong enough to control HIV viral load and pathology following vaccination.
Novel Vaccine Adjuvants: Members of the TNF/TNFR superfamily are involved in the induction and regulation of cellular and humoral immune responses. TNF superfamily ligands can induce the activation of a number of cell types including dendritic cells, B cells, and T cells. Dr. Stone is studying the use of CD40L and other members of the TNF Superfamily of ligands as immunostimulants and vaccine adjuvants. Molecules of interest include CD40L, GITRL, OX40L, 4-1BBL, RANKL, CD70, BAFF, and LIGHT.
- An important discovery has been the requirement by many TNF superfamily ligands for trimeric protein clustering to induce optimal activation of their receptors. In order to reduce clustering in a manner safe for vaccine development, Dr. Stone has fused the extracellular domains of TNF superfamily ligands with the body of spontaneously multimerizing proteins with trimeric arms, such as surfactant protein D (SP-D).
- In related studies, Dr. Stone's laboratory is testing the Epstein Barr Virus immunostimulatory protein LMP1 as a vaccine adjuvant approach. This involves mimicking the activity of receptors such as CD40 in a single molecule that is constitutively active.