Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation.
Viral infection or reactivation remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. We now show that infusions of single cytotoxic T lymphocyte (CTL) lines (5 x 10(6)-1.35 x 10(8) cells/m(2)) with specificity for 2 commonly detected viruses, Epstein-Barr virus (EBV) and adenovirus, can be safely administered to pediatric transplantation recipients receiving partially human leukocyte antigen-matched and haploidentical stem cell grafts (n = 13), without inducing graft-versus-host disease. The EBV-specific component of the CTLs expanded in vivo and persisted for more than 12 weeks, but the adenovirus-specific component only expanded in vivo in the presence of concomitant adenoviral infection. Nevertheless, adenovirus-specific T cells could be detected for at least 8 weeks in peripheral blood, even in CTL recipients without viral infection, provided the adenovirus-specific component of their circulating lymphocytes was first expanded by exposure to adenoviral antigens ex vivo. After infusion, none of these 13 high-risk recipients developed EBV-associated lymphoproliferative disease, while 2 of the subjects had resolution of their adenoviral disease. Hence, bispecific CTLs containing both EBV- and adenovirus-specific T cells can safely reconstitute an antigen responsive "memory" population of CTLs after human leukocyte antigen-mismatched stem cell transplantation and may provide antiviral activity. This trial was registered at www.clinicaltrials.gov as #NCT00590083.
Leen
Ann M
AM
Center for Cell and Gene Therapy and Departments of Pediatrics, Immunology, Medicine, and Virology, Baylor College of Medicine, Texas Children's Hospital and the Methodist Hospital, Houston, TX 77030, USA. amleen@txccc.org
Christin
Anne
A
Myers
Gary D
GD
Liu
Hao
H
Cruz
Conrad R
CR
Hanley
Patrick J
PJ
Kennedy-Nasser
Alana A
AA
Leung
Kathryn S
KS
Gee
Adrian P
AP
Krance
Robert A
RA
Brenner
Malcolm K
MK
Heslop
Helen E
HE
Rooney
Cliona M
CM
Bollard
Catherine M
CM
D000258:Adenovirus Infections, Human / Q000209:etiology / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D000260:Adenoviruses, Human / Q000235:genetics / Q000302:isolation & purification; D000293:Adolescent; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D020031:Epstein-Barr Virus Infections / Q000209:etiology / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification; D006650:Histocompatibility Testing; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D007223:Infant; D008212:Lymphocyte Depletion; D008297:Male; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation*; D014019:Tissue Donors; D014184:Transplantation, Homologous
D004279:DNA, Viral
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