Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease.
Adoptive transfer of Epstein Barr virus (EBV)-specific cytotoxic T-lymphocytes (EBV-CTLs) has shown that these cells persist in patients with EBV(+) Hodgkin lymphoma (HD) to produce complete tumor responses. Treatment failure, however, occurs if a subpopulation of malignant cells in the tumor lacks or loses expression of EBV antigens. We have therefore determined whether we could prepare EBV-CTLs that retained the antitumor activity conferred by their native receptor while expressing a chimeric antigen receptor (CAR) specific for CD30, a molecule highly and consistently expressed on malignant Hodgkin Reed-Sternberg cells. We made a CD30CAR and were able to express it on 26% (+/- 11%) and 22% (+/- 5%) of EBV-CTLs generated from healthy donors and HD patients, respectively. These CD30CAR(+) CTLs killed both autologous EBV(+) cells through their native receptor and EBV(-)/CD30(+) targets through their major histocompatibility complex (MHC)-unrestricted CAR. A subpopulation of activated T cells also express CD30, but the CD30CAR(+) CTLs did not impair cellular immune responses, probably because normal T cells express lower levels of the target antigen. In a xenograft model, CD30CAR(+) EBV-CTLs could be costimulated by EBV-infected cells and produce antitumor effects even against EBV(-)/CD30(+) tumors. EBV-CTLs expressing both a native and a chimeric antigen receptor may therefore have added value for treatment of HD.
Savoldo
Barbara
B
Center for Cell and Gene Therapy, Baylor College of Medicine, the Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA. bsavoldo@bcm.tmc.edu
Rooney
Cliona M
CM
Di Stasi
Antonio
A
Abken
Hinrich
H
Hombach
Andreas
A
Foster
Aaron E
AE
Zhang
Lan
L
Heslop
Helen E
HE
Brenner
Malcolm K
MK
Dotti
Gianpietro
G
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D018920:Coculture Techniques; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology; D006689:Hodgkin Disease / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007167:Immunotherapy; D017730:Ki-1 Antigen / Q000276:immunology* / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000378:metabolism*
D006649:Histocompatibility Antigens; D017730:Ki-1 Antigen; D050506:Mutant Chimeric Proteins; D011948:Receptors, Antigen, T-Cell