Abstract

We present a strategy for adoptive immunotherapy using T-lineage committed lymphoid precursor cells generated by Notch1-based culture. We found that allogeneic T-cell precursors can be transferred to irradiated individuals irrespective of major histocompatibility complex (MHC) disparities and give rise to host-MHC restricted and host-tolerant functional allogeneic T cells, improving survival in irradiated recipients as well as enhancing anti-tumor responses. T-cell precursors transduced to express a chimeric receptor targeting hCD19 resulted in significant additional anti-tumor activity, demonstrating the feasibility of genetic engineering of these cells. We conclude that ex vivo generated MHC-disparate T-cell precursors from any donor can be used universally for 'off-the-shelf' immunotherapy, and can be further enhanced by genetic engineering for targeted immunotherapy.

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Acknowledgements

This work was supported by grants HL69929, CA33049 and CA107096 from the National Institutes of Health (NIH), by awards from the Leukemia and Lymphoma Society, the Ryan Gibson Foundation, the Elsa U. Pardee Foundation, the Byrne Fund, the Emerald Foundation and The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research (M.R.M.v.d.B.). J.L.Z. is the recipient of a fellowship grant from the Lymphoma Research Foundation, J.C.M. and G.R. are supported by a Cancer Research Institute Pre-Doctoral Fellowship and by NIH MSTP grant GM07739, M.S. and J.C.M are supported by NIH grant CA40350, M.S., I.R. and J.C.M. are supported by NIH grant CA59350, and J.C.Z.-P. is supported by a Canada Research Chair in Developmental Immunology. Technical services provided by the MSKCC Small-Animal Imaging Core Facility, supported in part by NIH Small-Animal Imaging Research Program (SAIRP) grant R24 CA83084 and NIH Center grant P30 CA08748, are gratefully acknowledged. The authors would like to thank the staff of the Research Animal Resource Center for excellent animal care. A20, a B-cell lymphoma cell line derived from BALB/c mice, and Renca, a renal cell carcinoma cell line derived from BALB/c mice, were kindly provided by A. Houghton (Memorial Sloan Kettering Cancer Center).

Author information

Affiliations

  1. Department Immunology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.

    • Johannes L Zakrzewski
    • , David Suh
    • , Odette M Smith
    • , Christopher King
    • , Gabrielle L Goldberg
    • , Robert Jenq
    • , Amanda M Holland
    • , Jeremy Grubin
    • , Javier Cabrera-Perez
    • , Sydney X Lu
    • , Gabrielle Rizzuto
    • , Derek B Sant'Angelo
    •  & Marcel R M van den Brink
  2. Department of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.

    • John C Markley
    • , Isabelle Riviere
    •  & Michel Sadelain
  3. Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.

    • Robert Jenq
    • , Renier J Brentjens
    • , Michel Sadelain
    •  & Marcel R M van den Brink
  4. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.

    • Glenn Heller
  5. Department of Immunology, University of Toronto, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.

    • Juan Carlos Zúñiga-Pflücker
  6. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.

    • Chen Lu

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Contributions

J.L.Z designed experiments, performed tissue culture, in vivo bioluminescence imaging studies and flow cytometric studies, analyzed data, generated figures and wrote the manuscript. D.S., O.M.S., C.K., A.M.H., J.G. and J.C.-P. assisted with performance of T-cell precursor transfer and tumor experiments, hematopoietic stem cell sorting, organ harvests, GVHD scoring and monitoring of survival. J.C.M. generated vectors and designed experiments regarding genetic engineering of T-cell precursors, M.S. designed experiments regarding genetic engineering of T-cell precursors and analyzed data, R.J.B. constructed the 19z1 vector, I.R. provided the 19z1-specific antibody, G.R. performed ELISPOT studies, C.L. performed histopathological studies, G.H. performed statistical analyses, G.L.G., S.X.L. and R.J. analyzed data, D.B.S. and J.C.Z.-P. designed experiments and analyzed data, M.R.M.v.d.B. designed experiments, analyzed data, supervised the study and edited the manuscript.

Corresponding author

Correspondence to Marcel R M van den Brink.

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DOI

https://doi.org/10.1038/nbt1395

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