Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.
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.
Pule
Martin A
MA
Center for Cell and Gene Therapy, Baylor College of Medicine and The Methodist Hospital and Texas Children's Hospital, Houston, Texas 77030, USA.
Savoldo
Barbara
B
Myers
G Doug
GD
Rossig
Claudia
C
Russell
Heidi V
HV
Dotti
Gianpietro
G
Huls
M Helen
MH
Liu
Enli
E
Gee
Adrian P
AP
Mei
Zhuyong
Z
Yvon
Eric
E
Weiss
Heidi L
HL
Liu
Hao
H
Rooney
Cliona M
CM
Heslop
Helen E
HE
Brenner
Malcolm K
MK
D000293:Adolescent; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D009447:Neuroblastoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D051603:Recoverin / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism* / Q000821:virology
D051603:Recoverin