Our Science – Sabzevari Website

Helen Sabzevari, Ph.D.

Laboratory of Tumor Immunology and Biology Staff Scientist 10 Center Drive, MSC 1750 Bldg. 10, Rm 5B01 Bethesda, MD 20892 Phone:   301-496-7235 Fax:   Fax Number not listed E-Mail:   hs113z@nih.gov

Biography

Head, Molecular Immunology Group

Research

The Molecular Immunology Group studies the mechanism of T cell activation as it relates to vaccine therapy. We are also involved in studying the role of various gene products in both naive and memory T cell populations concerning such functions as cell cycle, apoptosis, and cytokine expression. Additionally, we are working to define mechanisms that relate to immune activation, immune regulation, and/or signaling pathways.

Vector-based Delivery of Tumor Antigens, T-cell Costimulation and Cytokines in the Induction of Immune Responses and Anti-Tumor Immunity: Experimental Systems. Two types of recombinant orthopox vectors are currently being evaluated for the delivery and expression of transgenes for tumor-associated antigens (TAAs), costimulatory molecules, and cytokines. These vectors are the replication competent vaccinia recombinants, and the replication defective avipox recombinants. Experimental studies have determined that the induction of an immune response to a given TAA can be amplified by priming the immune system with a recombinant vaccinia vector followed by multiple booster vaccinations with a recombinant avipox vector. These studies have formed the basis for clinical trials using diversified prime and boost vaccine strategies. Initial studies demonstrated that the insertion of the B7.1 costimulatory molecule transgene gene into an orthopox vector along with a TAA gene can greatly enhance the CD4 and CD8 responses to the TAA. We have now designed and studied recombinant orthopox vectors containing the following costimulatory molecule transgenes: B7.2, ICAM-1 LFA-3, and CD70. Analysis of these recombinants alone and in combinations has demonstrated that a TRIad of COstimulatory Molecules (B7.1, ICAM-1 and LFA-3; acronym TRICOM) will synergize to enhance T-cell responses to levels far greater than that achieved by any one or 2 costimulatory molecules. Recombinant vaccinia and avipox TRICOM vectors have been designed and are in the process of being analyzed; studies to date have demonstrated that when antigen-presenting cells (APC) are infected with TRICOM vectors and pulsed with peptide, the activated T-cells are markedly enhanced for production of type 1 cytokines, but do not undergo any enhanced level of apoptosis. Mechanistically, studies in TCR-transgenic mice are ongoing that indicate that upon activation, both naïve and memory T-cells actually acquire costimulatory molecules from the APC. Ongoing and planned studies are designed to determine if this phenomenon has either immunostimulatory or immunoregulatory implications, or both. Recombinant orthopox vectors have also been designed that contain the transgene for a model TAA (e.g., carcinoembryonic antigen, CEA) and 3 costimulatory molecule transgenes. These rV-CEA-TRICOM and avipox-CEA-TRICOM vectors are being evaluated in animal models to better form the basis for their subsequent use in clinical trials in patients with CEA-expressing carcinomas. Studies are ongoing and planned to better understand the interactions between the level of signal 1 (through the T-cell receptor) and the level of signal 2 (costimulatory signal(s)) in both the activation of naive T-cells or the induction and maintenance of memory T-cells. Other groups have previously shown that the use of recombinant cytokines such as GM-CSF and low dose IL-2 can enhance T-cell responses to a peptide as protein-based vaccine. We have now shown that the actual delivery of GM-CSF via an avipox-GM-CSF recombinant can lead to enhanced levels of APC, and duration of APC, in regional nodes as compared to the use of recombinant GM-CSF protein. Studies are now planned to determine how to better employ recombinant GM-CSF avipox vectors in vaccine strategies using protein or peptide immunogens and immunogens delivered through orthopox recombinant vectors, and will form the basis for subsequent use in clinical trials. Studies are ongoing and planned in experimental transgenic models to define and understand the synergy between vector-based delivery of signal 1, signal 2 (through 1 or multiple costimulatory molecules) and cytokines in the activation and/or regulation of both naive and memory T-cell responses, and in the induction of anti-tumor responses.

For a list of publications from the Molecular Immunology Group, see 'Links'.

This page was last updated on 9/3/2008.