Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation

Ekaterina Doubrovina, Banu Oflaz-Sozmen, Susan E. Prockop, Nancy A. Kernan, Sara Abramson, Julie Teruya-Feldstein, Cyrus Hedvat, Joanne F. Chou, Glenn Heller, Juliet N. Barker, Farid Boulad, Hugo Castro-Malaspina, Diane George, Ann Jakubowski, Guenther Koehne, Esperanza B. Papadopoulos, Andromachi Scaradavou, Trudy N. Small, Ramzi Khalaf, James W. YoungRichard J. O'Reilly

Research output: Contribution to journalArticlepeer-review

305 Scopus citations

Abstract

We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.

Original languageEnglish
Pages (from-to)2644-2656
Number of pages13
JournalBlood
Volume119
Issue number11
DOIs
StatePublished - 15 Mar 2012
Externally publishedYes

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