Mamta Kalra1, Ulrike Gerdemann1, Jessica D Luu1, Minthran C Ngo1, Ann M Leen2, Chrystal U Louis1, Cliona M Rooney3, Stephen Gottschalk4. 1. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; Departments of Pediatrics. 2. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; Departments of Pediatrics; Pathology and Immunology. 3. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; Departments of Pediatrics; Pathology and Immunology; Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA. 4. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; Departments of Pediatrics; Pathology and Immunology. Electronic address: stephen.gottschalk@stjude.org.
Abstract
BACKGROUND AIMS: EBV type II latency tumors, such as Hodgkin lymphoma (HL), Non-Hodgkin lymphoma (NHL) and nasopharyngeal carcinoma, express a limited array of EBV antigens including Epstein-Barr nuclear antigen (EBNA)1, latent membrane protein (LMP)1, LMP2, and BamH1-A right frame 1 (BARF1). Adoptive immunotherapy for these malignancies have focused on EBNA1, LMP1 and LMP2 because little is known about the cellular immune response to BARF1. METHODS: To investigate whether BARF1 is a potential T-cell immunotherapy target, we determined the frequency of BARF1-specific T-cell responses in the peripheral blood of EBV-seropositive healthy donor and patients with EBV-positive malignancies, mapped epitopes and evaluated the effector function of ex vivo-generated BARF1-specific T-cell lines. RESULTS: BARF1-specific T cells were present in the peripheral blood of 12/16 (75%) EBV-positive healthy donors and 13/20 (65%) patients with EBV-positive malignancies. Ex vivo expanded BARF1-specific T-cell lines contained CD4- and CD8-positive T-cell subpopulations, and we identified 23 BARF1 peptides, which encoded major histocompatibility complex class I- and/or II-restricted epitopes. Epitope mapping identified one human leukocyte antigen (HLA)-A*02-restricted epitope that was recognized by 50% of HLA-A*02, EBV-seropositive donors and one HLA-B*15(62)-restricted epitope. Exvivo expanded BARF1-specific T cells recognized and killed autologous, EBV-transformed lymphoblastoid cell lines and partially HLA-matched EBV-positive lymphoma cell lines. DISCUSSION: BARF1 should be considered as an immunotherapy target for EBV type II (and III) latency. Targeting BARF1, in addition to EBNA1, LMP1 and LMP2, has the potential to improve the efficacy of current T-cell immunotherapy approaches for these malignancies.
BACKGROUND AIMS: EBV type II latency tumors, such as Hodgkin lymphoma (HL), Non-Hodgkin lymphoma (NHL) and nasopharyngeal carcinoma, express a limited array of EBV antigens including Epstein-Barr nuclear antigen (EBNA)1, latent membrane protein (LMP)1, LMP2, and BamH1-A right frame 1 (BARF1). Adoptive immunotherapy for these malignancies have focused on EBNA1, LMP1 and LMP2 because little is known about the cellular immune response to BARF1. METHODS: To investigate whether BARF1 is a potential T-cell immunotherapy target, we determined the frequency of BARF1-specific T-cell responses in the peripheral blood of EBV-seropositive healthy donor and patients with EBV-positive malignancies, mapped epitopes and evaluated the effector function of ex vivo-generated BARF1-specific T-cell lines. RESULTS: BARF1-specific T cells were present in the peripheral blood of 12/16 (75%) EBV-positive healthy donors and 13/20 (65%) patients with EBV-positive malignancies. Ex vivo expanded BARF1-specific T-cell lines contained CD4- and CD8-positive T-cell subpopulations, and we identified 23 BARF1 peptides, which encoded major histocompatibility complex class I- and/or II-restricted epitopes. Epitope mapping identified one human leukocyte antigen (HLA)-A*02-restricted epitope that was recognized by 50% of HLA-A*02, EBV-seropositive donors and one HLA-B*15(62)-restricted epitope. Exvivo expanded BARF1-specific T cells recognized and killed autologous, EBV-transformed lymphoblastoid cell lines and partially HLA-matched EBV-positive lymphoma cell lines. DISCUSSION: BARF1 should be considered as an immunotherapy target for EBV type II (and III) latency. Targeting BARF1, in addition to EBNA1, LMP1 and LMP2, has the potential to improve the efficacy of current T-cell immunotherapy approaches for these malignancies.
Authors: Amy B Hont; Allison B Powell; Danielle K Sohai; Izabella K Valdez; Maja Stanojevic; Ashley E Geiger; Kajal Chaudhary; Ehsan Dowlati; Catherine M Bollard; Conrad Russell Y Cruz Journal: Mol Ther Date: 2022-02-09 Impact factor: 12.910
Authors: Xizhou Zhu; Alfredo Perales-Puchalt; Krzysztof Wojtak; Ziyang Xu; Kun Yun; Pratik S Bhojnagarwala; Devivasha Bordoloi; Daniel H Park; Kevin Liaw; Mamadou A Bah; Paul M Lieberman; Ebony N Gary; Ami Patel; David B Weiner Journal: Mol Ther Oncolytics Date: 2021-12-21 Impact factor: 6.311