Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma

Domenico Orlando, Evelina Miele, Biagio De Angelis, Marika Guercio, Iolanda Boffa, Matilde Sinibaldi, Agnese Po, Ignazio Caruana, Luana Abballe, Andrea Carai, Simona Caruso, Antonio Camera, Annemarie Moseley, Renate S Hagedoorn, Mirjam H M Heemskerk, Felice Giangaspero, Angela Mastronuzzi, Elisabetta Ferretti, Franco Locatelli, Concetta Quintarelli

Research output: Contribution to journalArticle

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. Cancer Res; 78(12); 3337-49. ©2018 AACR.

Original languageEnglish
Pages (from-to)3337-3349
Number of pages13
JournalCancer Research
Volume78
Issue number12
DOIs
Publication statusPublished - Jun 15 2018

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Adoptive Immunotherapy
Medulloblastoma
T-Lymphocytes
HLA-A Antigens
Caspase 9
Neoplasm Antigens
Brain Neoplasms
Immunotherapy
Neoplasms
Morbidity
Biopsy
Safety
Survival

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Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma. / Orlando, Domenico; Miele, Evelina; De Angelis, Biagio; Guercio, Marika; Boffa, Iolanda; Sinibaldi, Matilde; Po, Agnese; Caruana, Ignazio; Abballe, Luana; Carai, Andrea; Caruso, Simona; Camera, Antonio; Moseley, Annemarie; Hagedoorn, Renate S; Heemskerk, Mirjam H M; Giangaspero, Felice; Mastronuzzi, Angela; Ferretti, Elisabetta; Locatelli, Franco; Quintarelli, Concetta.

In: Cancer Research, Vol. 78, No. 12, 15.06.2018, p. 3337-3349.

Research output: Contribution to journalArticle

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, RS, Heemskerk, MHM, Giangaspero, F, Mastronuzzi, A, Ferretti, E, Locatelli, F & Quintarelli, C 2018, 'Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma', Cancer Research, vol. 78, no. 12, pp. 3337-3349. https://doi.org/10.1158/0008-5472.CAN-17-3140
Orlando, Domenico ; Miele, Evelina ; De Angelis, Biagio ; Guercio, Marika ; Boffa, Iolanda ; Sinibaldi, Matilde ; Po, Agnese ; Caruana, Ignazio ; Abballe, Luana ; Carai, Andrea ; Caruso, Simona ; Camera, Antonio ; Moseley, Annemarie ; Hagedoorn, Renate S ; Heemskerk, Mirjam H M ; Giangaspero, Felice ; Mastronuzzi, Angela ; Ferretti, Elisabetta ; Locatelli, Franco ; Quintarelli, Concetta. / Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma. In: Cancer Research. 2018 ; Vol. 78, No. 12. pp. 3337-3349.
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title = "Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma",
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. Cancer Res; 78(12); 3337-49. {\circledC}2018 AACR.",
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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

N1 - ©2018 American Association for Cancer Research.

PY - 2018/6/15

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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. Cancer Res; 78(12); 3337-49. ©2018 AACR.

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. Cancer Res; 78(12); 3337-49. ©2018 AACR.

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