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Immunology

IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia

Leukemia volume 29, pages 415–422 (2015)Cite this article

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Abstract

Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia (ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19+ tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL.

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Acknowledgements

HJP was supported by the National Health and Medical Research Council of Australia.

Author Contributions

HJP designed and performed the experiments, analyzed the data and prepared the manuscript. TJP and DGvL designed and performed the experiments and analyzed the data. KJC, JNB and RJB designed the experiments, analyzed the data and revised the manuscript. SAG designed the experiments, analyzed the data.

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Authors and Affiliations

  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA,

    H J Pegram, T J Purdon, D G van Leeuwen, S A Giralt, J N Barker & R J Brentjens

  2. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA,

    K J Curran

  3. Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA,

    S A Giralt & J N Barker

  4. Weill Cornell Medical College, New York, NY, USA

    S A Giralt & J N Barker

  5. Center for Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA,

    R J Brentjens

  6. Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA,

    R J Brentjens

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  1. H J Pegram
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Correspondence to R J Brentjens.

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Competing interests

RJB is a co-founder, stockholder, and consultant for Juno Therapeutics. The remaining authors declare no conflict of interest.

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Pegram, H., Purdon, T., van Leeuwen, D. et al. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 29, 415–422 (2015). https://doi.org/10.1038/leu.2014.215

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