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

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. 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 (patent awarded in 1998). A company, Argos Therapeutics was established in Durham, NC to commercialize this approach.

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.

Novel vaccine strategies: Research Question: How do we develop an effective vaccine strategy that is NOT time-, labor- and resource-intensive? Summary: A drawback of dendritic cell-based vaccination is that the process of harvesting, culturing and loading dendritic cells with antigens is time-, labor- and resource-intensive. We have demonstrated an innovative method of vaccination as a proof-of-concept in a study by loading mRNA encoding a tumor antigen onto whole blood cells. This approach circumvents the time-consuming cell culture and leukapheresis required for dendritic cell vaccines and can be completed in 1 to 2 hours instead of 7 to 9 days. 

Oncolytic poliovirus immunotherapy: Research Question: Does regional cytoxicity with oncolytic poliovirus stimulate innate immune events that promote an in situ vaccine effect? Summary: Matthias Gromeier has pioneered an oncolytic poliovirus (OncPV) therapy, PVSRIPO

Representative Publications:
  • Mitchell, DA; Batich, KA; Gunn, MD; Huang, MN; Sanchez-Perez, L; Nair, SK; Congdon, KL; Reap, EA; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015;519:366-369.  Abstract
  • Pratico, ED; Feger, BJ; Watson, MJ; Sullenger, BA; Bowles, DE; Milano, CA; Nair, S. RNA-mediated reprogramming of primary adult human dermal fibroblasts into c-kit+ cardiac progenitor cells. Stem Cells and Development. 2015;  Abstract
  • Brown, MC; Dobrikova, EY; Dobrikov, MI; Walton, RW; Gemberling, SL; Nair, SK; Desjardins, A; Sampson, JH; Friedman, HS; Friedman, AH; Tyler, DS; Bigner, DD; Gromeier, M. Oncolytic polio virotherapy of cancer. Cancer. 2014;120:3277-3286.  Abstract
  • Nair, SK; De Leon, G; Boczkowski, D; Schmittling, R; Xie, W; Staats, J; Liu, R; Johnson, LA; Weinhold, K; Archer, GE; Sampson, JH; Mitchell, DA. Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20:2684-2694.  Abstract
  • Nair, SK; Tomaras, GD; Sales, AP; Boczkowski, D; Chan, C; Plonk, K; Cai, Y; Dannull, J; Kepler, TB; Pruitt, SK; Weinhold, KJ. High-throughput identification and dendritic cell-based functional validation of MHC class I-restricted Mycobacterium tuberculosis epitopes. Scientific Reports. 2014;4:4632.  Abstract
  • Phua, KK; Boczkowski, D; Dannull, J; Pruitt, S; Leong, KW; Nair, SK. Whole blood cells loaded with messenger RNA as an anti-tumor vaccine. Advanced healthcare materials. 2014;3:837-842.  Abstract
  • Phua, KK; Staats, HF; Leong, KW; Nair, SK. Intranasal mRNA nanoparticle vaccination induces prophylactic and therapeutic anti-tumor immunity. Scientific Reports. 2014;4:5128.  Abstract
  • Lee, J; Boczkowski, D; Nair, S. Programming human dendritic cells with mRNA. Methods in molecular biology (Clifton, N.J.). 2013;969:111-125.  Abstract
  • Nair, S; Aldrich, AJ; McDonnell, E; Cheng, Q; Aggarwal, A; Patel, P; Williams, MM; Boczkowski, D; Lyerly, HK; Morse, MA; Devi, GR. Immunologic targeting of FOXP3 in inflammatory breast cancer cells. PloS one. 2013;8:e53150.  Abstract
  • Phua, KK; Leong, KW; Nair, SK. Transfection efficiency and transgene expression kinetics of mRNA delivered in naked and nanoparticle format. Journal of Controlled Release. 2013;166:227-233.  Abstract
  • Pratico, ED; Sullenger, BA; Nair, SK. Identification and characterization of an agonistic aptamer against the T cell costimulatory receptor, OX40. Nucleic Acid Therapeutics. 2013;23:35-43.  Abstract
  • Nair, S; Archer, GE; Tedder, TF. Isolation and generation of human dendritic cells. Current Protocols in Immunology. 2012;Chapter 7:Unit7.32.  Abstract
  • Pruitt, SK; Boczkowski, D; de Rosa, N; Haley, NR; Morse, MA; Tyler, DS; Dannull, J; Nair, S. Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. European Journal of Immunology. 2011;41:3553-3563.  Abstract
  • Boczkowski, D; Lee, J; Pruitt, S; Nair, S. Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy. Cancer Gene Therapy. 2009;16:900-911.  Abstract
  • Dollins, CM; Nair, S; Boczkowski, D; Lee, J; Layzer, JM; Gilboa, E; Sullenger, BA. Assembling OX40 aptamers on a molecular scaffold to create a receptor-activating aptamer. Chemistry & Biology. 2008;15:675-682.  Abstract
  • Lee, J; Dollins, CM; Boczkowski, D; Sullenger, BA; Nair, S. Activated B cells modified by electroporation of multiple mRNAs encoding immune stimulatory molecules are comparable to mature dendritic cells in inducing in vitro antigen-specific T-cell responses. Immunology. 2008;125:229-240.  Abstract
  • 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
  • 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
  • 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
  • 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
  • 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
  • Nair, SK; Morse, M; Boczkowski, D; Cumming, RI; Vasovic, L; Gilboa, E; Lyerly, HK. Induction of tumor-specific cytotoxic T lymphocytes in cancer patients by autologous tumor RNA-transfected dendritic cells. Annals of Surgery. 2002;235:540-549.  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
  • 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
  • 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, 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
  • 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