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Cytotoxic T cells transduced with chimeric anti-CD19 receptors prevent engraftment of primary lymphoblastic leukemia in vivo

Leukemia volume 24, pages 1080–1084 (2010)Cite this article

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Despite considerable advances in the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), 10–20% of children and >60% of adults still fail the available therapies.1 Hematopoietic stem cell transplantation (HSCT) has contributed to favorable outcomes in high-risk or recurrent ALL in both pediatric and adult populations; however, overt relapses after transplant are currently incurable. Patients at high risk for a subsequent relapse can now be identified by quantification of minimal residual disease (MRD) before transplantation,2 facilitating assessment of novel strategies to maintain remission and improve prognosis. Adoptive transfer of cytotoxic T cells (CTLs) is one means to enhance the therapeutic potential of HSCT. Although alloreactive donor lymphocytes can exert potent effects against myeloid leukemias,3 attempts to exploit unmanipulated donor T cells for the treatment of high-risk ALL have had limited success,3 indicating the lack of immunogenic targets for graft-versus-leukemia responses in this malignancy.

One alternative to harness the cytotoxic potential of T cells is to redirect their specificity to leukemia cells by genetic engineering with chimeric antigen-specific receptors (CARs). CARs consist of an antibody-derived recognition domain, linked to signaling molecules that activate T cells upon interaction with cells expressing the respective target antigen on their surface.4 CD19 is an attractive target for immunological therapies in BCP-ALL because it is expressed at high densities on most malignant B cells and expression is restricted to the B-cell lineage. CARs against CD19 have now been generated by various groups and have been demonstrated to mediate potent T-cell effector functions against CD19-expressing malignant cells in vitro and in vivo.5 Specifically, human T cells endowed with CD19-specific CARs have been shown to effectively eradicate human CD19+ tumor xenografts in immuno-deficient mouse models.5 So far, in vivo evidence for the antileukemia activity of CD19-specific T cells has been restricted to established tumor cell lines. Primary leukemia cells more closely mimic the heterogeneity of the disease in humans and allow to differentiate between individual subgroups with variable biological risk profiles. In this study, we have investigated the in vivo sensitivity of human leukemic bone marrow (BM) to adoptive immunotherapy with gene-modified CD19-specific T cells.

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Acknowledgements

This work was supported by the German José Carreras Leukemia Foundation (DJCLS R 06/44v, to CR and JV) and EU funding provided for the ‘CHILDHOPE’ network program under the terms of an EU Framework 6 grant (to CR and MP).

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany

    S Landmeier, B Altvater, S Pscherer, J Meltzer, M Hotfilder, H Juergens & C Rossig

  2. Department of Histopathology, Great Ormond Street Hospital, London, UK

    N Sebire

  3. Department of Haematology, University College London, London, UK

    M Pule

  4. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA

    J Vera

  5. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK

    J Vormoor

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  1. S Landmeier
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Correspondence to C Rossig.

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Landmeier, S., Altvater, B., Pscherer, S. et al. Cytotoxic T cells transduced with chimeric anti-CD19 receptors prevent engraftment of primary lymphoblastic leukemia in vivo. Leukemia 24, 1080–1084 (2010). https://doi.org/10.1038/leu.2010.38

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