Personalized adoptive immunotherapy for patients with EBV-associated tumors and complications: Evaluation of novel naturally processed and presented EBV-derived T-cell epitopes
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Maren Bieling1,2, Sabine Tischer1,2, Ulrich Kalinke3, Rainer Blasczyk1,2, Søren Buus4, Britta Maecker-Kolhoff2,5 and Britta Eiz-Vesper1,2
1Institute for Transfusion Medicine, Hannover Medical School (MHH), Hanover, Germany
2Integrated Research and Treatment Center (IFB-Tx), MHH, Hanover, Germany
3Division of Experimental Infection Research, TWINCORE, Centre of Experimental and Clinical Infection Research, MHH, Hanover, Germany
4Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
5Department of Pediatric Hematology and Oncology, MHH, Hanover, Germany
Britta Eiz-Vesper, email: [email protected]
Keywords: Epstein-Barr virus; post-transplant lymphoproliferative disease; adoptive T-cell immunotherapy; cytotoxic T-cell epitopes; T-cell monitoring
Received: October 03, 2017 Accepted: December 04, 2017 Published: December 21, 2017
Morbidity and mortality of immunocompromised patients are increased by primary infection with or reactivation of Epstein-Barr virus (EBV), possibly triggering EBV+ post-transplant lymphoproliferative disease (PTLD). Adoptive transfer of EBV-specific cytotoxic T cells (EBV-CTLs) promises a non-toxic immunotherapy to effectively prevent or treat these complications.
To improve immunotherapy and immunomonitoring this study aimed at identifying and evaluating naturally processed and presented HLA-A*03:01-restricted EBV-CTL epitopes as immunodominant targets. More than 15000 peptides were sequenced from EBV-immortalized B cells transduced with soluble HLA-A*03:01, sorted using different epitope prediction tools and eleven candidates were preselected. T2 and Flex-T peptide-binding and dissociation assays confirmed the stability of peptide-MHC complexes. Their immunogenicity and clinical relevance were evaluated by assessing the frequencies and functionality of EBV-CTLs in healthy donors (n > 10) and EBV+ PTLD-patients (n = 5) by multimer staining, Eli- and FluoroSpot assays. All eleven peptides elicited EBV-CTL responses in the donors. Their clinical applicability was determined by small-scale T-cell enrichment using Cytokine Secretion Assay and immunophenotyping. Mixtures of these peptides when added to the EBV Consensus pool revealed enhanced stimulation and enrichment efficacy. These EBV-specific epitopes broadening the repertoire of known targets will improve manufacturing of clinically applicable EBV-CTLs and monitoring of EBV-specific T-cell responses in patients.
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