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Towards ‘off-the-shelf’ genetically modified T cells: prolonging functional engraftment in mice by CD8 veto T cells

Leukemia volume 32, pages 1038–1040 (2018)Cite this article

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Targeted immunotherapy using T cells bearing chimeric antigen receptors (CAR T cells) is a promising treatment of end-stage leukemia patients.1, 2, 3, 4 Currently, CAR-T must be produced from autologous cells, complicating their production and delaying their administration to the patients, thereby preventing their application to fast-progressing diseases such as acute leukemias. Production of allogeneic universal donor T cells, as an ‘off-the-shelf’ reagent, could significantly facilitate CAR T-cell therapy and greatly increase the number of benefiting patients.5 To this end, one must overcome host-mediated rejection and potential graft versus host disease (GvHD) that are mediated by allogeneic cells. While the risk of GvHD may be adequately addressed by gene editing of the endogenous T-cell receptor (TCR), suicide gene transduction or selection of non-GvHD inducing cells,6, 7, 8, 9 graft-rejection represents a more difficult barrier. Here, we present a method for preventing rejection of HLA mismatched CAR-T cells, while preserving their selective anti-tumor activity, by using donor-derived mouse anti-3rd-party central memory CD8 veto cells (Tcm), previously shown to be devoid of GvH and capable of inducing tolerance to allografts.10, 11

The immune-regulatory properties of anti-3rd-party veto Tcm were established in fully mismatched T-cell-depleted bone marrow transplantation (TDBMT), under reduced intensity conditioning (RIC).10, 11 However, whether Tcm can act as a tolerizing agent independently of allogeneic TDBMT, without support of the CD34+ veto cell compartment, remains unknown.

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Acknowledgements

This work was supported in part by grants from Cell Source Ltd. and from Roberto and Renata Ruhman.

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  1. N Or-Geva and R Gidron-Budovsky: 1These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    N Or-Geva, R Gidron-Budovsky, L Radomir, Y Edelstein, A K Singh, R Sidlik-Muskatel, E Ophir, E Bachar-Lustig & Y Reisner

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  1. N Or-Geva
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Correspondence to Y Reisner.

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YR is a shareholder and a consultant to Cell Source LTD.

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Or-Geva, N., Gidron-Budovsky, R., Radomir, L. et al. Towards ‘off-the-shelf’ genetically modified T cells: prolonging functional engraftment in mice by CD8 veto T cells. Leukemia 32, 1038–1040 (2018). https://doi.org/10.1038/leu.2017.332

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