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. ©2018 AACR.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 12 Pg. 3337-3349 (06 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29615432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• HLA-A2 Antigen
• PRAME protein, human
• Receptors, Antigen, T-Cell
• CASP9 protein, human
• Caspase 9

Topics

• Adolescent
• Animals
• Antigens, Neoplasm (immunology, metabolism)
• Caspase 9 (genetics, immunology)
• Cell Line, Tumor
• Cerebellar Neoplasms (immunology, pathology, therapy)
• Child
• Child, Preschool
• Coculture Techniques
• Cohort Studies
• Female
• Genes, Transgenic, Suicide (genetics, immunology)
• HLA-A2 Antigen (immunology, metabolism)
• Humans
• Immunotherapy, Adoptive (methods)
• Male
• Medulloblastoma (immunology, pathology, therapy)
• Mice
• Receptors, Antigen, T-Cell (genetics, immunology, metabolism)
• T-Lymphocytes (immunology, metabolism, transplantation)
• Treatment Outcome
• Xenograft Model Antitumor Assays