title: Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma.
abstract: We generated MHC-independent chimeric antigen receptors (CARs) directed to the GD2 antigen expressed by neuroblastoma tumor cells and treated patients with this disease. Two distinguishable forms of this CAR were expressed in EBV-specific cytotoxic T lymphocytes (EBV-CTLs) and activated T cells (ATCs). We have previously shown that EBV-CTLs expressing GD2-CARs (CAR-CTLs) circulated at higher levels than GD2-CAR ATCs (CAR-ATCs) early after infusion, but by 6 weeks, both subsets became low or undetectable. We now report the long-term clinical and immunologic consequences of infusions in 19 patients with high-risk neuroblastoma: 8 in remission at infusion and 11 with active disease. Three of 11 patients with active disease achieved complete remission, and persistence of either CAR-ATCs or CAR-CTLs beyond 6 weeks was associated with superior clinical outcome. We observed persistence for up to 192 weeks for CAR-ATCs and 96 weeks for CAR-CTLs, and duration of persistence was highly concordant with the percentage of CD4(+) cells and central memory cells (CD45RO(+)CD62L(+)) in the infused product. In conclusion, GD2-CAR T cells can induce complete tumor responses in patients with active neuroblastoma; these CAR T cells may have extended, low-level persistence in patients, and such persistence was associated with longer survival. This study is registered at www.clinialtrials.gov as #NCT00085930.
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA. culouis@txch.org
authors: Chrystal U
authors: CU
authors: Louis
authors: Barbara
authors: B
authors: Savoldo
authors: Gianpietro
authors: G
authors: Dotti
authors: Martin
authors: M
authors: Pule
authors: Eric
authors: E
authors: Yvon
authors: G Doug
authors: GD
authors: Myers
authors: Claudia
authors: C
authors: Rossig
authors: Heidi V
authors: HV
authors: Russell
authors: Oumar
authors: O
authors: Diouf
authors: Enli
authors: E
authors: Liu
authors: Hao
authors: H
authors: Liu
authors: Meng-Fen
authors: MF
authors: Wu
authors: Adrian P
authors: AP
authors: Gee
authors: Zhuyong
authors: Z
authors: Mei
authors: Cliona M
authors: CM
authors: Rooney
authors: Helen E
authors: HE
authors: Heslop
authors: Malcolm K
authors: MK
authors: Brenner
mesh_terms: D000293:Adolescent; D019264:Adoptive Transfer / Q000379:methods*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology; D019046:Bone Marrow Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D001859:Bone Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D005732:Gangliosides / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D008297:Male; D018365:Neoplasm, Residual / Q000235:genetics / Q000276:immunology / Q000628:therapy; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D055815:Young Adult
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D005732:Gangliosides; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C019403:ganglioside, GD2