Advertisement

Clinical MedicineIn-Press PreviewImmunologyTransplantation Free access | 10.1172/JCI121127

Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplant

Susan Prockop, Ekaterina Doubrovina, Stephanie Suser, Glenn Heller, Juliet Barker, Parastoo Dahi, Miguel A. Perales, Esperanza Papadopoulos, Craig Sauter, Hugo Castro-Malaspina, Farid Boulad, Kevin J. Curran, Sergio Giralt, Boglarka Gyurkocza, Katharine C. Hsu, Ann Jakubowski, Alan M. Hanash, Nancy A. Kernan, Rachel Kobos, Guenther Koehne, Heather Landau, Doris Ponce, Barbara Spitzer, James W. Young, Gerald Behr, Mark Dunphy, Sofia Haque, Julie Teruya-Feldstein, Maria Arcila, Christine Moung, Susan Hsu, Aisha Hasan, and Richard J. O'Reilly

Find articles by Prockop, S. in: JCI | PubMed | Google Scholar

Find articles by Doubrovina, E. in: JCI | PubMed | Google Scholar

Find articles by Suser, S. in: JCI | PubMed | Google Scholar

Find articles by Heller, G. in: JCI | PubMed | Google Scholar

Find articles by Barker, J. in: JCI | PubMed | Google Scholar |

Find articles by Dahi, P. in: JCI | PubMed | Google Scholar

Find articles by Perales, M. in: JCI | PubMed | Google Scholar

Find articles by Papadopoulos, E. in: JCI | PubMed | Google Scholar

Find articles by Sauter, C. in: JCI | PubMed | Google Scholar

Find articles by Castro-Malaspina, H. in: JCI | PubMed | Google Scholar

Find articles by Boulad, F. in: JCI | PubMed | Google Scholar

Find articles by Curran, K. in: JCI | PubMed | Google Scholar |

Find articles by Giralt, S. in: JCI | PubMed | Google Scholar

Find articles by Gyurkocza, B. in: JCI | PubMed | Google Scholar

Find articles by Hsu, K. in: JCI | PubMed | Google Scholar

Find articles by Jakubowski, A. in: JCI | PubMed | Google Scholar

Find articles by Hanash, A. in: JCI | PubMed | Google Scholar

Find articles by Kernan, N. in: JCI | PubMed | Google Scholar |

Find articles by Kobos, R. in: JCI | PubMed | Google Scholar

Find articles by Koehne, G. in: JCI | PubMed | Google Scholar

Find articles by Landau, H. in: JCI | PubMed | Google Scholar |

Find articles by Ponce, D. in: JCI | PubMed | Google Scholar |

Find articles by Spitzer, B. in: JCI | PubMed | Google Scholar

Find articles by Young, J. in: JCI | PubMed | Google Scholar

Find articles by Behr, G. in: JCI | PubMed | Google Scholar |

Find articles by Dunphy, M. in: JCI | PubMed | Google Scholar

Find articles by Haque, S. in: JCI | PubMed | Google Scholar

Find articles by Teruya-Feldstein, J. in: JCI | PubMed | Google Scholar

Find articles by Arcila, M. in: JCI | PubMed | Google Scholar

Find articles by Moung, C. in: JCI | PubMed | Google Scholar

Find articles by Hsu, S. in: JCI | PubMed | Google Scholar

Find articles by Hasan, A. in: JCI | PubMed | Google Scholar

Find articles by O'Reilly, R. in: JCI | PubMed | Google Scholar

First published November 5, 2019 - More info

J Clin Invest. https://doi.org/10.1172/JCI121127.
Copyright © 2019, American Society for Clinical Investigation
First published November 5, 2019 - Version history
Abstract

Background: Adoptive transfer of donor-derived EBV-specific T-cells (EBV-CTLs) can eradicate EBV associated lymphomas post hematopoietic cell (HCT) or solid organ (SOT) transplants but is not available for most patients.

Methods: We developed a 3rd-party, allogeneic, off-the-shelf bank of 330 GMP grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (N=33) or SOT (N=13) with established EBV associated lymphomas, who failed rituximab therapy, with 3rd-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation.

Results: The EBV-CTLs did not induce significant toxicities or graft injury. One patient developed grade I skin GVHD requiring topical therapy. Complete and sustained partial remissions were achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, overall survival was 88.9% and 81.8% respectively at 1 year. Although only 1/11 patients (9.1%) with progression of disease (POD) after cycle 1 who received additional EBV-CTLs from the same donor survived, 3 of 5 with POD subsequently treated with EBV-CTLs from a different donor achieved CR or durable PR (60%) and survive > 1 year. Maximal responses were achieved after a median of 2 cycles.

Conclusions: Third party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab refractory EBV-associated lymphoma post transplant.

Phase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, Food and Drug Administration and National Marrow Donor Program.

This work was supported through NIH grants CA23766, NIH R21CA162002, Aubrey Fund, The Claire Tow Foundation, Major Family Foundation, Max Cure Foundation, Richard “Rick” J. EIsemann Pediatric Research Fund, Banbury Foundation, Edith Robertson Foundation, Larry Smead Foundation. In June 2015 Atara Biotherapeutics licensed the EBV-CTL bank and is developing this as ATA-129.

Supplemental material

View

Version history
  • Version 1 (November 5, 2019): In-Press Preview
Advertisement
Advertisement