Smita Kesavan Nair, PhD

AddThis

Print

email this


Associate Professor of Surgery
Associate Professor in Pathology
Department / Division:
Surgery / Surgical Sciences
Address:
Room 1077, Msrb Ii
106 Research Drive
Durham, NC 27710
Office Telephone:
(919) 681-2180
Training:
  • PhD, UniversityTennessee Knoxville*, 1993
Research Interests:
RESEARCH INTERESTS

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
Representative Publications:
  • Nair, S; Boczkowski, D; Fassnacht, M; Pisetsky, D; Gilboa, E. Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Research. 2007;67:371-380.  Abstract
  • Fecci, PE; Sweeney, AE; Grossi, PM; Nair, SK; Learn, CA; Mitchell, DA; Cui, X; Cummings, TJ; Bigner, DD; Gilboa, E; Sampson, JH. Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells. Clinical Cancer Research. 2006;12:4294-4305.  Abstract
  • Hess, PR; Boczkowski, D; Nair, SK; Snyder, D; Gilboa, E. Vaccination with mRNAs encoding tumor-associated antigens and granulocyte-macrophage colony-stimulating factor efficiently primes CTL responses, but is insufficient to overcome tolerance to a model tumor/self antigen. Cancer Immunology Immunotherapy. 2006;55:672-683.  Abstract
  • Dannull, J; Nair, S; Su, Z; Boczkowski, D; DeBeck, C; Yang, B; Gilboa, E; Vieweg, J. Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand. Blood. 2005;105:3206-3213.  Abstract
  • Fassnacht, M; Lee, J; Milazzo, C; Boczkowski, D; Su, Z; Nair, S; Gilboa, E. Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy. Clinical Cancer Research. 2005;11:5566-5571.  Abstract
  • Lee, J; Fassnacht, M; Nair, S; Boczkowski, D; Gilboa, E. Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Research. 2005;65:11156-11163.  Abstract
  • Liao, X; Li, Y; Bonini, C; Nair, S; Gilboa, E; Greenberg, PD; Yee, C. Transfection of RNA encoding tumor antigens following maturation of dendritic cells leads to prolonged presentation of antigen and the generation of high-affinity tumor-reactive cytotoxic T lymphocytes. Molecular Therapy. 2004;9:757-764.  Abstract
  • Nair, S; Boczkowski, D; Moeller, B; Dewhirst, M; Vieweg, J; Gilboa, E. Synergy between tumor immunotherapy and antiangiogenic therapy. Blood. 2003;102:964-971.  Abstract
  • Nair, S; McLaughlin, C; Weizer, A; Su, Z; Boczkowski, D; Dannull, J; Vieweg, J; Gilboa, E. Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation. Journal of Immunology. 2003;171:6275-6282.  Abstract
  • Santulli-Marotto, S; Nair, SK; Rusconi, C; Sullenger, B; Gilboa, E. Multivalent RNA aptamers that inhibit CTLA-4 and enhance tumor immunity. Cancer Research. 2003;63:7483-7489.  Abstract
  • Zhao, Y; Boczkowski, D; Nair, SK; Gilboa, E. Inhibition of invariant chain expression in dendritic cells presenting endogenous antigens stimulates CD4+ T-cell responses and tumor immunity. Blood. 2003;102:4137-4142.  Abstract
  • Faiola, B; Doyle, C; Gilboa, E; Nair, S. Influence of CD4 T cells and the source of major histocompatibility complex class II-restricted peptides on cytotoxic T-cell priming by dendritic cells. Immunology. 2002;105:47-55.  Abstract
  • Boczkowski, D; Nair, SK; Nam, JH; Lyerly, HK; Gilboa, E. Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Research. 2000;60:1028-1034.  Abstract
  • Morse, MA; Nair, S; Fernandez-Casal, M; Deng, Y; St Peter, M; Williams, R; Hobeika, A; Mosca, P; Clay, T; Cumming, RI; Fisher, E; Clavien, P; Proia, AD; Niedzwiecki, D; Caron, D; Lyerly, HK. Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer. Journal of Clinical Oncology. 2000;18:3883-3893.  Abstract
  • Nair, SK; Heiser, A; Boczkowski, D; Majumdar, A; Naoe, M; Lebkowski, JS; Vieweg, J; Gilboa, E. Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. Nature Medicine. 2000;6:1011-1017.  Abstract
  • Thornburg, C; Boczkowski, D; Gilboa, E; Nair, SK. Induction of cytotoxic T lymphocytes with dendritic cells transfected with human papillomavirus E6 and E7 RNA: implications for cervical cancer immunotherapy. Journal of Immunotherapy. 2000;23:412-418.  Abstract
  • Nair, S; Wearsch, PA; Mitchell, DA; Wassenberg, JJ; Gilboa, E; Nicchitta, CV. Calreticulin displays in vivo peptide-binding activity and can elicit CTL responses against bound peptides. Journal of Immunology. 1999;162:6426-6432.  Abstract
  • Mitchell, DA; Nair, SK; Gilboa, E. Dendritic cell/macrophage precursors capture exogenous antigen for MHC class I presentation by dendritic cells. European Journal of Immunology. 1998;28:1923-1933.  Abstract
  • Morse, MA; Lyerly, HK; Gilboa, E; Thomas, E; Nair, SK. Optimization of the sequence of antigen loading and CD40-ligand-induced maturation of dendritic cells. Cancer Research. 1998;58:2965-2968.  Abstract
  • Nair, SK; Boczkowski, D; Morse, M; Cumming, RI; Lyerly, HK; Gilboa, E. Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA. Nature Biotechnology. 1998;16:364-369.  Abstract
  • Wong, C; Morse, M; Nair, SK. Induction of primary, human antigen-specific cytotoxic T lymphocytes in vitro using dendritic cells pulsed with peptides. Journal of Immunotherapy. 1998;21:32-40.  Abstract
  • Ashley, DM; Faiola, B; Nair, S; Hale, LP; Bigner, DD; Gilboa, E. Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors. Journal of Experimental Medicine. 1997;186:1177-1182.  Abstract
  • Nair, SK; Boczkowski, D; Snyder, D; Gilboa, E. Antigen-presenting cells pulsed with unfractionated tumor-derived peptides are potent tumor vaccines. European Journal of Immunology. 1997;27:589-597.  Abstract
  • Nair, SK; Snyder, D; Rouse, BT; Gilboa, E. Regression of tumors in mice vaccinated with professional antigen-presenting cells pulsed with tumor extracts. International Journal of Cancer. 1997;70:706-715.  Abstract
  • Boczkowski, D; Nair, SK; Snyder, D; Gilboa, E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. Journal of Experimental Medicine. 1996;184:465-472.  Abstract
  • Nair, SK; Snyder, D; Gilboa, E. Cells treated with TAP-2 antisense oligonucleotides are potent antigen-presenting cells in vitro and in vivo. Journal of Immunology. 1996;156:1772-1780.  Abstract
  • Babu, JS; Nair, S; Kanda, P; Rouse, BT. Priming for virus-specific CD8+ but not CD4+ cytotoxic T lymphocytes with synthetic lipopeptide is influenced by acylation units and liposome encapsulation. Vaccine. 1995;13:1669-1676.  Abstract
  • Kanangat, S; Nair, S; Babu, JS; Rouse, BT. Expression of cytokine mRNA in murine splenic dendritic cells and better induction of T cell-derived cytokines by dendritic cells than by macrophages during in vitro costimulation assay using specific antigens. Journal of Leukocyte Biology. 1995;57:310-316.  Abstract
  • Nair, S; Buiting, AM; Rouse, RJ; Van Rooijen, N; Huang, L; Rouse, BT. Role of macrophages and dendritic cells in primary cytotoxic T lymphocyte responses. International Immunology. 1995;7:679-688.  Abstract
  • Bowen, JC; Nair, SK; Reddy, R; Rouse, BT. Cholera toxin acts as a potent adjuvant for the induction of cytotoxic T-lymphocyte responses with non-replicating antigens. Immunology. 1994;81:338-342.  Abstract
  • Rouse, RJ; Nair, SK; Lydy, SL; Bowen, JC; Rouse, BT. Induction in vitro of primary cytotoxic T-lymphocyte responses with DNA encoding herpes simplex virus proteins. Journal of Virology. 1994;68:5685-5689.  Abstract
  • Banks, TA; Nair, S; Rouse, BT. Recognition by and in vitro induction of cytotoxic T lymphocytes against predicted epitopes of the immediate-early protein ICP27 of herpes simplex virus. Journal of Virology. 1993;67:613-616.  Abstract
  • Nair, S; Babu, JS; Dunham, RG; Kanda, P; Burke, RL; Rouse, BT. Induction of primary, antiviral cytotoxic, and proliferative responses with antigens administered via dendritic cells. Journal of Virology. 1993;67:4062-4069.  Abstract
  • Nair, S; Zhou, F; Reddy, R; Huang, L; Rouse, BT. Soluble proteins delivered to dendritic cells via pH-sensitive liposomes induce primary cytotoxic T lymphocyte responses in vitro. Journal of Experimental Medicine. 1992;175:609-612.  Abstract
  • Nair, S; Zhou, X; Huang, L; Rouse, BT. Class I restricted CTL recognition of a soluble protein delivered by liposomes containing lipophilic polylysines. Journal of Immunological Methods. 1992;152:237-243.  Abstract
  • Reddy, R; Zhou, F; Nair, S; Huang, L; Rouse, BT. In vivo cytotoxic T lymphocyte induction with soluble proteins administered in liposomes. Journal of Immunology. 1992;148:1585-1589.  Abstract