Antitumor activity and long-term fate of chimeric antigen receptor–positive T cells in patients with neuroblastoma

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 (ATC...

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Bibliographic Details
Published in:Blood 2011-12, Vol.118 (23), p.6050-6056
Main Authors: Louis, Chrystal U., Savoldo, Barbara, Dotti, Gianpietro, Pule, Martin, Yvon, Eric, Myers, G. Doug, Rossig, Claudia, Russell, Heidi V., Diouf, Oumar, Liu, Enli, Liu, Hao, Wu, Meng-Fen, Gee, Adrian P., Mei, Zhuyong, Rooney, Cliona M., Heslop, Helen E., Brenner, Malcolm K.
Format: Article
Language:English
Subjects:
Adolescent
Adoptive Transfer - methods
Antigens, Tumor-Associated, Carbohydrate - immunology
Biological and medical sciences
Bone Marrow Neoplasms - genetics
Bone Marrow Neoplasms - immunology
Bone Marrow Neoplasms - therapy
Bone Neoplasms - genetics
Bone Neoplasms - immunology
Bone Neoplasms - therapy
Cell Line, Tumor
Child
Child, Preschool
Female
Follow-Up Studies
Gangliosides - immunology
Gene Therapy
Genetic Therapy - methods
Hematologic and hematopoietic diseases
Humans
Immunobiology
Immunologic Memory - immunology
Male
Medical sciences
Neoplasm, Residual - genetics
Neoplasm, Residual - immunology
Neoplasm, Residual - therapy
Neuroblastoma - genetics
Neuroblastoma - immunology
Neuroblastoma - therapy
Neurology
Receptors, Antigen, T-Cell - genetics
Receptors, Antigen, T-Cell - immunology
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - immunology
T-Lymphocytes, Cytotoxic - immunology
Tumors of the nervous system. Phacomatoses
Young Adult
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Description
Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2011-05-354449