TY - JOUR
T1 - Adoptive immunotherapy using prame-specific t cells in medulloblastoma
AU - Orlando, Domenico
AU - Miele, Evelina
AU - De Angelis, Biagio
AU - Guercio, Marika
AU - Boffa, Iolanda
AU - Sinibaldi, Matilde
AU - Po, Agnese
AU - Caruana, Ignazio
AU - Abballe, Luana
AU - Carai, Andrea
AU - Caruso, Simona
AU - Camera, Antonio
AU - Moseley, Annemarie
AU - Hagedoorn, Renate S.
AU - Heemskerk, Mirjam H.M.
AU - Giangaspero, Felice
AU - Mastronuzzi, Angela
AU - Ferretti, Elisabetta
AU - Locatelli, Franco
AU - Quintarelli, Concetta
PY - 2018/6/15
Y1 - 2018/6/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-3140
DO - 10.1158/0008-5472.CAN-17-3140
M3 - Article
AN - SCOPUS:85048707363
VL - 78
SP - 3337
EP - 3349
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 12
ER -