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Immunology, Inflammation, and Immunotherapy Laboratory

Photo of Smita Kesavan Nair, PhD

Smita Kesavan Nair, PhD

Office: MRSB-2 106 Research Drive, Room 1077 Durham, NC 27710
Phone: 919-681-2180

Scientific Focus

I am a cellular immunologist with 22 years of experience in immunology and immunotherapy. My PhD training was in Dr. Barry Rouse’s lab at the University of Tennessee, Knoxville and my post-doctoral training was in Dr. Eli Gilboa’s lab at Duke University Medical Center.

The research in our laboratory focuses on the designing and testing of novel vaccines against cancer and viral infections using murine and human assay systems. In a pioneering study, our group demonstrated that dendritic cells, pulsed with unfractionated total RNA isolated from tumor cells, stimulates tumor immunity both in murine tumor models and in vitro human assays. A large number of our pre-clinical strategies have been translated into Phase I clinical trials in cancer patients. The focus and challenge of our laboratory, both at the preclinical and clinical level, is to augment the clinical benefit associated with immunotherapy. Our long-term goals are as follows: (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 (radiotherapy, chemotherapy, immunotoxin therapy, and oncolytic poliovirus therapy).

Selected Achievements

 

In the News

 

Accomplishments

  • Researchers in the lab invented the RNA transfected dendritic cell-based vaccination approach. We have been instrumental in establishing the first GMP-production facility for dendritic cell-based cancer vaccines for Phase I clinical trials at Duke.
  • Manuscript in Science Translational Medicine, Sep 20 2017, describing how poliovirus induces antitumor immunity

Research projects

 

1. 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 vitro human assays. This led to the patent on the use of RNA transfected dendritic cells as vaccines (awarded in 1998). In 1999, Argos Therapeutics was established in Durham, NC to commercialize this approach.

2. 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.

3. Novel vaccine strategies

Research Question: How do we develop an effective vaccine strategy that is NOT time-, labor-, or 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 whole blood cell mRNA vaccine is as potent as the dendritic cell RNA vaccine in a mouse tumor model of melanoma.

4. 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, PhD, has pioneered an oncolytic poliovirus (OncPV) therapy, PVSRIPO, which selectively targets and eliminates malignant cells. A first-in-human Phase-1 study with PVSRIPO at Duke University has shown remarkable promise in patients with recurrent glioblastoma multiforme (GBM), a uniformly lethal disease. In collaboration with the Gromeier lab we are testing the following hypothesis: 1] regional OncPV therapy initiates immune events associated with oncolysis and inflammation; 2] these immune events could potentially lead to an in situ vaccine effect and a systemic immune response. We will test this hypothesis in immunocompetent mouse models.

Current research in the Immunology, Inflammation, and Immunotherapy Laboratory examines:

  1. Dendritic cell vaccines using tumor-antigen encoding RNA (mRNA, total tumor RNA, amplified tumor mRNA)
  2. Local immune receptor modulation using mRNA that encodes for antibodies, receptor-ligands, cytokines, chemokines, and Toll-like receptors (current target list: CTLA4, GITR, PD1, TIM3, LAG3, OX40, and 41BB)
  3. Combination therapies for cancer: cytotoxic therapy (radiation, chemo, and oncolytic poliovirus therapy) with dendritic cell-based vaccines and immune checkpoint blockade
  4. Adoptive T cell therapy using tumor RNA-transfected dendritic cells to expand tumor-specific T cells ex vivo
  5. Adoptive T cell therapy using PSMA CAR (chimeric antigen receptor) RNA-transfected T cells
  6. Direct injection of tumor antigen encoding RNA (targeting antigens to dendritic cells in vivo using nanoparticles and aptamers)

Latest Publications

Force, J, Howie, LJ, Abbott, SE, Bentley, R, Marcom, PK, Kimmick, G, Westbrook, K, Sammons, SL, Parks, M, Topping, DL, Emerson, R, Broadwater, G, Hyslop, T, Blackwell, KL, and Nair, SK. "Early Stage HER2-Positive Breast Cancers Not Achieving a pCR From Neoadjuvant Trastuzumab- or Pertuzumab-Based Regimens Have an Immunosuppressive Phenotype." Clinical Breast Cancer 18, no. 5 (October 2018): 410-417.

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Desjardins, A, Gromeier, M, Herndon, JE, Beaubier, N, Bolognesi, DP, Friedman, AH, Friedman, HS, McSherry, F, Muscat, AM, Nair, S, Peters, KB, Randazzo, D, Sampson, JH, Vlahovic, G, Harrison, WT, McLendon, RE, Ashley, D, and Bigner, DD. "Recurrent Glioblastoma Treated with Recombinant Poliovirus." The New England Journal of Medicine 379, no. 2 (July 2018): 150-161.

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Gromeier, M, and Nair, SK. "Recombinant Poliovirus for Cancer Immunotherapy." Annual review of medicine 69 (January 2018): 289-299.

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Reap, EA, Suryadevara, CM, Batich, KA, Sanchez-Perez, L, Archer, GE, Schmittling, RJ, Norberg, PK, Herndon, JE, Healy, P, Congdon, KL, Gedeon, PC, Campbell, OC, Swartz, AM, Riccione, KA, Yi, JS, Hossain-Ibrahim, MK, Saraswathula, A, Nair, SK, Dunn-Pirio, AM, Broome, TM, Weinhold, KJ, Desjardins, A, Vlahovic, G, McLendon, RE, Friedman, AH, Friedman, HS, Bigner, DD, Fecci, PE, Mitchell, DA, and Sampson, JH. "Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma." Cancer research 78, no. 1 (January 2018): 256-264.

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