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.

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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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. (2018). Adoptive immunotherapy using prame-specific t cells in medulloblastoma. Cancer Research, 78(12), 3337-3349. https://doi.org/10.1158/0008-5472.CAN-17-3140