CD1d-restricted NKT cells with invariant TCR? chains (iNKT cells) are a unique and conserved component of the mammalian immune system. Studies in mice have shown dramatic in vivo effects of iNKT cell activators, such as the CD1d-presented glycolipid antigen ?-galactosylceramide (?GalCer), in a wide variety of animal models, but despite remarkable therapeutic effects with iNKT cell activators in murine models of cancer and other diseases, this area has been slow to progress to more advanced clinical development. This application addresses issues that are likely to be major limitations in advancing iNKT cell-based therapeutics, and seeks to provide practical solutions to these impediments. We hypothesize that attempts to move iNKT cell therapeutics into the clinic for applications such as cancer immunotherapy or as vaccine adjuvants have been slowed by three specific issues, all of which will be directly addressed by the current proposal. The first is the suboptimal design of synthetic iNKT cell activators, which we will overcome using recent discoveries from our work on the structure-activity relationship of ?GalCer analogues. The second issue is the tendency of iNKT cell agonists to induce deletion and hypo-responsiveness of the responding cells (?anergy?), making them at best ?single shot? therapeutics. We will use recently developed novel glycolipid delivery methods to overcome this limitation. We also propose studies based on recent gene expression profiling in iNKT cells to identify the cell surface receptors that control post-activation anergy, which will provide mechanistic insights into the anergic response and strategies to overcome it. A third issue addressed by the proposal relates to the inadequacy of standard mouse models for development of potential iNKT cell therapeutics, for which we will implement human CD1d knock-in mice as the first practical, humanized model for in vivo evaluation of iNKT cell-based immunotherapies. Overall, this competing renewal application proposes innovative solutions to major impediments in the ongoing effort to harness the potential of iNKT cell-based therapeutics. Successful completion of the aims of the proposal should advance our understanding of iNKT cell biology, while also helping to drive progress in the area of cancer immunotherapy.

Public Health Relevance

We propose studies that will develop highly efficient methods for using synthetic glycolipids to activate and modulate the functions of a type of lymphocyte known as invariant Natural Killer T (iNKT) cells. The proposed work is strongly focused on the goal of developing clinically relevant iNKT cell-based therapies for cancer and other diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Rothermel, Annette L
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Albert Einstein College of Medicine
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Chennamadhavuni, Divya; Saavedra-Avila, Noemi Alejandra; Carreño, Leandro J et al. (2018) Dual Modifications of ?-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity. Cell Chem Biol 25:571-584.e8
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Chandra, Shilpi; Gray, James; Kiosses, William B et al. (2018) Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae. Nat Commun 9:4279
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Carreño, Leandro J; Saavedra-Ávila, Noemí A; Porcelli, Steven A (2016) Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents. Clin Transl Immunology 5:e69
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Wen, Xiangshu; Kim, Seil; Xiong, Ran et al. (2015) A Subset of CD8??+ Invariant NKT Cells in a Humanized Mouse Model. J Immunol 195:1459-69
Birkholz, Alysia M; Girardi, Enrico; Wingender, Gerhard et al. (2015) A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-? Production. J Immunol 195:924-33

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