'Off-the-shelf' allogeneic antigen-specific adoptive T-cell therapy for the treatment of multiple EBV-associated malignancies. Issue 2 (15th February 2021)

• Record Type: Journal Article
• Authors: Sinha, Debottam; Srihari, Sriganesh; Beckett, Kirrliee; Le Texier, Laetitia; Solomon, Matthew; Panikkar, Archana; Ambalathingal, George R; Lekieffre, Lea; Crooks, Pauline; Rehan, Sweera; Neller, Michelle A.; Smith, Corey; Khanna, Rajiv
• Is Part Of: Journal for immunotherapy of cancer. Volume 9:Issue 2(2021)
• Publication Date: 2021-02-15
• Subjects: immunity -- cellular -- immunotherapy -- immunotherapy -- adoptive -- lymphocytes -- tumor-infiltrating -- t-lymphocytes; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-001608
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : 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.