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Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15

Nature Medicine volume 9, pages 279–286 (2003)Cite this article

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Abstract

The genetic transfer of antigen receptors provides a means to rapidly generate autologous tumor-reactive T lymphocytes. However, recognition of tumor antigens by cytotoxic T cells is only one step towards effective cancer immunotherapy. Other crucial biological prerequisites must be fulfilled to expand tumor-reactive T cells that retain a functional phenotype, including in vivo cytolytic activity and the ability to travel to tumor sites without prematurely succumbing to apoptosis. We show that these requirements are met by expanding peripheral blood T cells genetically targeted to the CD19 antigen in the presence of CD80 and interleukin-15 (IL-15). T cells expanded in the presence of IL-15 uniquely persist in tumor-bearing severe combined immunodeficiency (SCID)-Beige mice and eradicate disseminated intramedullary tumors. Their anti-tumor activity is further enhanced by in vivo co-stimulation. In addition, transduced T cells from patients with chronic lymphocytic leukemia (CLL) effectively lyse autologous tumor cells. These findings strongly support the clinical feasibility of this therapeutic strategy.

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Figure 1: 19z1-transduced T cells specifically lyse CD19+ tumor cells.
Figure 2: Rapid expansion of 19z1+ T cells using AAPCs expressing CD19 and CD80 with exogenous IL-15.
Figure 3: Eradication of established Raji tumors in SCID-Beige mice by 19z1+CD8+ T cells expanded on AAPCs with exogenous IL-15.
Figure 4: Tumor cell eradication by 19z1+ T cells is dependent on in vivo T-cell co-stimulation.
Figure 5: 51Cr-release assays of 19z1 (♦, ▪)- and Pz1 (⋄, □)-transduced T cells, derived from patients with CLL, targeting autologous tumor cells.

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  • 10 February 2003

    This was incorrect in AOP version but corrected in print. Added NIH grant AI44926 to acknowledgments as per note.

Notes

  1. NOTE: In the version of this article initially published online, NIH grant AI44926 was omitted from the acknowledgments. This mistake has been corrected for the HTML and print versions of the article.

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Acknowledgements

This work was supported by US National Institutes of Health grants CA-59350, CA-86438, CA-08748, CA-83084 and AI44926; the Translational and Integrative Medicine Research Fund at the Memorial Sloan-Kettering Cancer Center; the Lymphoma Research Foundation (formerly the Cure for Lymphoma Foundation; fellowship award to R.J.B.); the Goodwin ETC fund; Golfers Against Cancer; and US Department of Energy grant ER-62039.*Footnote 1

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Authors and Affiliations

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

    Renier J. Brentjens, Jean-Baptiste Latouche, Elmer Santos, Michael C. Gong, Clay Lyddane, Mark Weiss, Isabelle Rivière & Michel Sadelain

  2. Department of Nuclear Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Elmer Santos & Steven Larson

  3. Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Clay Lyddane, Isabelle Rivière & Michel Sadelain

  4. Department of the Gene Transfer and Somatic Cell Engineering Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Isabelle Rivière & Michel Sadelain

  5. Department of Immunology, Hospital for Special Surgery, Weill Medical College and Graduate School of Cornell University, New York, New York, USA

    Francesc Marti & Philip D. King

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Correspondence to Michel Sadelain.

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Brentjens, R., Latouche, JB., Santos, E. et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9, 279–286 (2003). https://doi.org/10.1038/nm827

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