PMID- 33589524 OWN - NLM STAT- MEDLINE DCOM- 20211215 LR - 20211215 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 2 DP - 2021 Feb TI - 'Off-the-shelf' allogeneic antigen-specific adoptive T-cell therapy for the treatment of multiple EBV-associated malignancies. LID - 10.1136/jitc-2020-001608 [doi] LID - e001608 AB - BACKGROUND: Epstein-Barr virus (EBV), an oncogenic human gammaherpesvirus, is associated with a wide range of human malignancies of epithelial and B-cell origin. Recent studies have demonstrated promising safety and clinical efficacy of allogeneic 'off-the-shelf' virus-specific T-cell therapies for post-transplant viral complications. METHODS: Taking a clue from these studies, we developed a highly efficient EBV-specific T-cell expansion process using a replication-deficient AdE1-LMPpoly vector that specifically targets EBV-encoded nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2), expressed in latency II malignancies. RESULTS: These allogeneic EBV-specific T cells efficiently recognized human leukocyte antigen (HLA)-matched EBNA1-expressing and/or LMP1 and LMP2-expressing malignant cells and demonstrated therapeutic potential in a number of in vivo models, including EBV lymphomas that emerged spontaneously in humanized mice following EBV infection. Interestingly, we were able to override resistance to T-cell therapy in vivo using a 'restriction-switching' approach, through sequential infusion of two different allogeneic T-cell therapies restricted through different HLA alleles. Furthermore, we have shown that inhibition of the programmed cell death protein-1/programmed death-ligand 1 axis in combination with EBV-specific T-cell therapy significantly improved overall survival of tumor-bearing mice when compared with monotherapy. CONCLUSION: These findings suggest that restriction switching by sequential infusion of allogeneic T-cell therapies that target EBV through distinct HLA alleles may improve clinical response. CI - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. FAU - Sinha, Debottam AU - Sinha D AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Srihari, Sriganesh AU - Srihari S AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Beckett, Kirrliee AU - Beckett K AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Le Texier, Laetitia AU - Le Texier L AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Solomon, Matthew AU - Solomon M AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Panikkar, Archana AU - Panikkar A AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Ambalathingal, George R AU - Ambalathingal GR AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Lekieffre, Lea AU - Lekieffre L AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Crooks, Pauline AU - Crooks P AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Rehan, Sweera AU - Rehan S AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Neller, Michelle A AU - Neller MA AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Smith, Corey AU - Smith C AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Khanna, Rajiv AU - Khanna R AUID- ORCID: 0000-0003-2241-0353 AD - Immunology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia rajiv.khanna@qimr.edu.au. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (EBV-associated membrane antigen, Epstein-Barr virus) RN - 0 (Epstein-Barr Virus Nuclear Antigens) RN - 0 (HLA Antigens) RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Viral Matrix Proteins) RN - O5GA75RST7 (EBV-encoded nuclear antigen 1) SB - IM MH - Animals MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Epstein-Barr Virus Infections/immunology/*therapy MH - Epstein-Barr Virus Nuclear Antigens/*immunology MH - Female MH - HLA Antigens MH - Herpesvirus 4, Human/*immunology MH - Humans MH - Immune Checkpoint Inhibitors/*administration & dosage/pharmacology MH - Lymphoma/immunology/therapy/*virology MH - Mice MH - T-Lymphocytes/immunology/*transplantation MH - Transplantation, Homologous MH - Viral Matrix Proteins/*immunology MH - Xenograft Model Antitumor Assays PMC - PMC7887372 OTO - NOTNLM OT - adoptive OT - cellular OT - immunity OT - immunotherapy OT - lymphocytes OT - t-lymphocytes OT - tumor-infiltrating COIS- Competing interests: CS and RK hold international patents on EBV vaccines and immunotherapy, which have been licensed to Atara Biotherapeutics. RK and CS act as consultants for Atara Biotherapeutics. RK is on the Scientific Advisory Board of Atara Biotherapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. EDAT- 2021/02/17 06:00 MHDA- 2021/12/16 06:00 PMCR- 2021/02/15 CRDT- 2021/02/16 06:02 PHST- 2021/01/10 00:00 [accepted] PHST- 2021/02/16 06:02 [entrez] PHST- 2021/02/17 06:00 [pubmed] PHST- 2021/12/16 06:00 [medline] PHST- 2021/02/15 00:00 [pmc-release] AID - jitc-2020-001608 [pii] AID - 10.1136/jitc-2020-001608 [doi] PST - ppublish SO - J Immunother Cancer. 2021 Feb;9(2):e001608. doi: 10.1136/jitc-2020-001608.