Smita Kesavan Nair, PhD

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Associate Professor of Surgery
Associate Professor in Pathology
Department / Division:
Surgery / Surgical Sciences
Address:
Room 1077, Msrb-2
106 Research Drive
Durham, NC 27710
Office Telephone:
(919) 681-2180
Training:
  • PhD, UniversityTennessee Knoxville*, 1993
Research Interests:
RESEARCH INTERESTS - Nair laboratory

I have 22 years of experience in the field of cancer vaccines and immunotherapy and I am an accomplished T cell immunologist. I started working with dendritic cells during my PhD training at the University of Tennessee, Knoxville in the laboratory of Dr. Barry Rouse. My doctoral research involved various aspects of antigen processing and presentation, in particular the role of dendritic cells as specialized antigen presenting cells, with emphasis on Herpes simplex virus. I joined Dr. Eli Gilboa’s lab at Duke University Medical Center in 1993 and worked as a post-doc for 3 years prior to becoming independent at Duke. I have gained national and an international reputation as a leader in the field of T cell immunity, specifically in the induction of T cell responses by dendritic cells.

The current emphasis of my research program is the development of a multipronged approach for cancer therapy. Our long-term goals are to: (1) evaluate the combined effects of individual strategies; (2) extend the clinical exploration to multiple cancers; and (3) combine immunotherapy and immune modulation with targeted cytotoxic therapy (specifically, oncolytic poliovirus).

Dendritic cells transfected with RNA as cancer vaccines: Research Question: Can we develop a novel vaccine strategy that is translatable and broadly applicable to all cancer patients, including patients with low tumor burden? Summary: We tested the hypotheses that: 1] Immunization with a broad repertoire of  tumor antigens isolated form cancer cells is superior to using defined tumor antigens. 2] Loading antigen on DCs in the form of tumor mRNA is highly effective and provides unique advantages over other forms of tumor antigen, specifically, the ability to amplify the antigenic content of a small number of tumor cells. In a pioneering study, our group demonstrated that dendritic cells loaded with unfractionated total RNA isolated from tumor cells stimulates tumor immunity both in murine tumor models and in in vitro human assays. To render this innovative approach applicable to all cancer patients, protocols were developed for the generation of unlimited supply of tumor antigens for therapy using only a few tumor cells. I am a key inventor of the landmark invention: the use of RNA transfected dendritic cells as vaccines (patent awarded in 1998). In 1999, a company, Argos Therapeutics (formerly Merix Biosciences) was established in Durham, NC to commercialize this approach. Argos Therapeutics started a Phase 3 trial in patients with renal cancer in 2013 and went public in February 2014.

Modulation of immune responses to enhance tumor-specific immunity: Research Question: How can the therapeutic benefit for patients treated with RNA-transfected dendritic cells be improved? Summary: Modulating immune responses by blocking inhibitory immune receptors and activating stimulatory immune receptors on T cells enhances tumor-specific immunity. Systemic administration of antibodies (Abs) targeting inhibitory immune receptors enhanced the stimulation of immune responses in mice. However, clinical use of such Abs is limited by toxicity. We have developed an approach for local modulation of immune responses by delivering RNA encoding immune modulating proteins (Abs or receptor-binding ligands) regionally at the site of T cell activation. In preclinical studies, anti-tumor immunity was enhanced with no evidence of autoimmunity, when mice were immunized with dendritic cells transfected with RNA encoding Abs targeting the two immune receptors: GITR (glucocorticoid-induced TNFR-related gene) or CTLA-4. The approach for local modulation of human CTLA-4 and GITR is ready for clinical implementation in patients with prostate cancer and breast cancer.

Novel vaccine strat

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 : an official journal of the American Association for 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 : an official journal of the American Association for 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 (Baltimore, Md. : 1950). 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 (Baltimore, Md. : 1950). 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. The 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. The 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 (Baltimore, Md. : 1950). 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. The 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 (Baltimore, Md. : 1950). 1992;148:1585-1589.  Abstract