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Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma

Nature Medicine volume 14, pages 1264–1270 (2008)Cite this article

Abstract

Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor–associated antigens do not survive long term and have limited antitumor activity in vivo, in part because such tumor cells typically lack the appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor–associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells.

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Figure 1: Transduction of CTLs and ATCs with GD2-specific CARs.
Figure 2: Immunophenotypes of CAR-transduced CTLs and ATCs.
Figure 3: In vivo persistence of infused CAR-CTLs versus CAR-ATCs in peripheral blood as determined by real-time quantitative PCR.
Figure 4: Reactivation of CAR-CTLs ex vivo.
Figure 5: Resolution of neuroblastoma in subjects 3 and 6 after infusion of genetically engineered T cells.

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Acknowledgements

Maloney murine leukemia virus–based vector was generously provided by R.C. Mulligan (Harvard Stem Cell Institute). This work was supported by grant PO1 CA94237 from the US National Institutes of Health, the General Clinical Research Centers at Baylor College of Medicine (RR00188) and a Doris Duke Distinguished Clinical Scientist Award to H.E.H.

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Authors and Affiliations

  1. Center for Cell and Gene Therapy, Baylor College of Medicine and The Methodist Hospital and Texas Children's Hospital, 6621 Fannin Street, Houston, 77030, Texas, USA

    Martin A Pule, Barbara Savoldo, G Doug Myers, Claudia Rossig, Heidi V Russell, Gianpietro Dotti, M Helen Huls, Enli Liu, Adrian P Gee, Zhuyong Mei, Eric Yvon, Cliona M Rooney, Helen E Heslop & Malcolm K Brenner

  2. Department of Pediatrics, Baylor College of Medicine, 6621 Fannin Street, Houston, 77030, Texas, USA

    G Doug Myers, Heidi V Russell, Adrian P Gee, Cliona M Rooney, Helen E Heslop & Malcolm K Brenner

  3. Department of Medicine, Baylor College of Medicine, 6621 Fannin Street, Houston, 77030, Texas, USA

    Gianpietro Dotti, Adrian P Gee, Helen E Heslop & Malcolm K Brenner

  4. Biostatistics Core of the Dan L Duncan Cancer Center, Baylor College of Medicine, 6621 Fannin Street, Houston, 77030, Texas, USA

    Heidi L Weiss & Hao Liu

  5. Department of Virology, Baylor College of Medicine, 6621 Fannin Street, Houston, 77030, Texas, USA

    Cliona M Rooney

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  1. Martin A Pule
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Contributions

This study was developed and designed by M.A.P., C.M.R., H.E.H. and M.K.B. The principal investigators on the clinical trial were G.D.M. and H.V.R. M.A.P. and C.R. performed the preclinical studies. M.A.P. and Z.M. manufactured the clinical vectors, and M.A.P. and G.D. designed the vectors and developed the gene transfer monitoring studies. B.S., G.D., E.L. and E.Y. performed the PCR and immune reconstitution studies. H.L.W. and H.L. provided statistical support. C.M.R., M.H.H. and B.S. supervised CTL and ATC preparation, and A.P.G. supervised quality assurance. B.S., G.D. C.M.R., H.E.H. and M.K.B. contributed to the writing of the paper.

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Correspondence to Malcolm K Brenner.

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Pule, M., Savoldo, B., Myers, G. et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14, 1264–1270 (2008). https://doi.org/10.1038/nm.1882

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