Chimeric immune receptors (CIRs) specific to JC virus for immunotherapy in progressive multifocal leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is a deadly brain disease caused by the polyomavirus JC (JCV). The aim of this study is to develop 'designer T cells' armed with anti-JCV TCR-based chimeric immune receptors (CIRs) by gene modification for PML immunotherapy. Two T cell lines specific to two dominant CTL epitopes derived from JCV VP1 protein (termed p36 and p100) from an HLA-A0201+PML survivor were generated for TCR cloning. Two distinct dominant TCR alpha chains (Vα6 and Vα12) and a unique TCR beta chain (Vβ5.1) were cloned from the p36-specific cell line, while only one alpha (Vα8.6) and one beta (Vβ2) chains were dominant in the p100-specific line. Retroviral constructs encoding CIRs were created with the extracellular domains of TCR α and β chains fused to the transmembrane and cytoplasmic portions of CD3ζ (VαCαCD3ζ or VβCβCD3ζ). Cellular expression and screening for binding specific peptide-HLA-A0201 tetramer confirmed the reactivity of the p100 TCRαβ and of one of the two pairs of p36 TCRαβ (Vα12 and Vβ5.1). Functional tests confirmed CIR-expressing T cells secreted cytokines and expressed potent cytotoxicity on contact with A0201+B-lymphoblastoid line loaded with peptides and/or with HLA-A0201+cells expressing native JCV VP1 protein. In conclusion, anti-JCV designer T cells were generated.

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