Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A-02+ DAOY cells as well as primary HLA-A-02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell- related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A-02+ medulloblastoma. Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells.

Adoptive immunotherapy using prame-specific t cells in medulloblastoma / Orlando, D.; Miele, E.; De Angelis, B.; Guercio, M.; Boffa, I.; Sinibaldi, M.; Po, A.; Caruana, I.; Abballe, L.; Carai, A.; Caruso, S.; Camera, A.; Moseley, A.; Hagedoorn, R. S.; Heemskerk, M. H. M.; Giangaspero, F.; Mastronuzzi, A.; Ferretti, E.; Locatelli, F.; Quintarelli, C.. - In: CANCER RESEARCH. - ISSN 0008-5472. - 78:12(2018), pp. 3337-3349. [10.1158/0008-5472.CAN-17-3140]

Adoptive immunotherapy using prame-specific t cells in medulloblastoma

De Angelis B.;Caruso S.;Quintarelli C.
2018

Abstract

Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A-02+ DAOY cells as well as primary HLA-A-02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell- related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A-02+ medulloblastoma. Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells.
2018
Adoptive immunotherapy using prame-specific t cells in medulloblastoma / Orlando, D.; Miele, E.; De Angelis, B.; Guercio, M.; Boffa, I.; Sinibaldi, M.; Po, A.; Caruana, I.; Abballe, L.; Carai, A.; Caruso, S.; Camera, A.; Moseley, A.; Hagedoorn, R. S.; Heemskerk, M. H. M.; Giangaspero, F.; Mastronuzzi, A.; Ferretti, E.; Locatelli, F.; Quintarelli, C.. - In: CANCER RESEARCH. - ISSN 0008-5472. - 78:12(2018), pp. 3337-3349. [10.1158/0008-5472.CAN-17-3140]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/810404
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