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IMMUNOTHERAPY

A nano-engager for iNKT cells in cancer

Nature Cancer volume 1, pages 1032–1034 (2020)Cite this article

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Invariant natural killer T cells (iNKT cells) are innate-like CD1d-restricted T cells that have NK cell–like properties and bear an invariant T cell receptor (iTCR). iNKT cells have shown potential for cancer immunotherapy. A study now shows that stabilization of the iTCR–CD1d complex via a single-chain bi-specific antibody stimulates iNKT cell–mediated anti-tumor immunity.

Early attempts to exploit iNKT cells in clinical trials employed the highly specific natural glycolipid ligand of iNKT cells presented by CD1d: α-galactosylceramide (α-GalCer)4,5,6 (Fig. 1a). This glycolipid-based therapy stimulates a type 1 helper iNKT cell response (anti-pathogen, anti-tumor and pro-inflammatory) as well as a type 2 helper iNKT cell response (antibody-inducing and immunoregulatory) and thus initiates broad immune responses1,2,3,4,5,6,8. The administration of α-GalCer via an intravenous bolus produced immunostimulatory effects on iNKT cells in advanced cancers and other cancers but yielded minimal anti-tumor responses in phase 1 clinical trials8. This led to a switch in delivery strategy toward the use of various versions of monocyte-derived dendritic-like cells (DCs) pre-loaded with α-GalCer2,4,5,6,8. The use of more-mature anti-tumor (type 1 helper iNKT cell)–biasing DCs led to objective clinical responses, which increased optimism for the development of these approaches4,5,6. However, α-GalCer and its derivatives are short-lived in vivo and very insoluble, which makes their formulations more challenging1,2,3,4,5,6,9. Moreover, therapies based on autologous α-GalCer-pre-loaded DCs remain complex, time-consuming and costly4,5,6.

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Fig. 1: iNKT cell–related therapies.

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Authors and Affiliations

  1. Department of Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Mark A. Exley, Thomas Gensollen & Richard S. Blumberg

  2. University of Manchester, Manchester, UK

    Mark A. Exley

  3. Imvax, Philadelphia, PA, USA

    Mark A. Exley

  4. Agentus, Lexington, MA, USA

    Mark A. Exley

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  1. Mark A. Exley
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  2. Thomas Gensollen
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  3. Richard S. Blumberg
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Correspondence to Mark A. Exley or Richard S. Blumberg.

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Competing interests

M.A.E. is employed by Imvax, a cancer vaccine–based company, and acts as consultant for Agentus, a company developing iNKT cell–based therapies.

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Exley, M.A., Gensollen, T. & Blumberg, R.S. A nano-engager for iNKT cells in cancer. Nat Cancer 1, 1032–1034 (2020). https://doi.org/10.1038/s43018-020-00138-9

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