Personalized adoptive immunotherapy for patients with EBVassociated tumors and complications: Evaluation of novel naturally processed and presented EBV-derived T-cell epitopes

TY - JOUR

T1 - Personalized adoptive immunotherapy for patients with EBVassociated tumors and complications

T2 - Evaluation of novel naturally processed and presented EBV-derived T-cell epitopes

AU - Bieling, Maren

AU - Tischer, Sabine

AU - Kalinke, Ulrich

AU - Blasczyk, Rainer

AU - Buus, Søren

AU - Maecker-Kolhoff, Britta

AU - Eiz-Vesper, Britta

PY - 2018/1

Y1 - 2018/1

N2 - 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.

AB - 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.

KW - Adoptive T-cell immunotherapy

KW - Cytotoxic T-cell epitopes

KW - Epstein-Barr virus

KW - Post-transplant lymphoproliferative disease

KW - T-cell monitoring

U2 - 10.18632/oncotarget.23531

DO - 10.18632/oncotarget.23531

M3 - Journal article

C2 - 29435138

AN - SCOPUS:85040454442

SN - 1949-2553

VL - 9

SP - 4737

EP - 4757

JO - Oncotarget

JF - Oncotarget

IS - 4

ER -