Abstract
Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fully humanized mice after EBV/B95-8 or EBV/M81 infections the effects of a clinically used PD-1 blocker. Fifteen to 17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with two types of EBV laboratory strains expressing firefly luciferase. Dynamic optical imaging analyses showed systemic EBV infections and this triggered vigorous human CD8+ T cell expansion. Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice. ICI promoted Ki67+CD30+CD20+EBER+PD-L1+ PTLD with central nervous system (CNS) involvement, mirroring EBV+ CNS PTLD in humans. PD-1 blockade was associated with lower frequencies of circulating T cells in blood and with a profound collapse of CD4+ T cells in lymphatic tissues. Mice treated with pembrolizumab showed an escalation of exhausted T cells expressing TIM-3, and LAG-3 in tissues, higher levels of several human cytokines in plasma and high densities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD.
Highlights
EBV is an oncogenic g-herpesvirus associated with around 2% of all human cancers such as hematologic and epithelial malignancies [1]
Mice infected with B95-8/fLuc treated with pembrolizumab or PBS showed comparable body weights (Figure 1D), while mice infected with M81/fLuc treated with high dose (HD) pembrolizumab showed weight loss compared with the other arms (Figure 1E)
At the baseline analyses before immune checkpoint inhibition (ICI) treatment (2 wpi), EBV infection levels assessed by Bioluminescence Imaging (BLI) analyses were comparable, and over time showed dynamic changes in intensities and bio-distribution
Summary
EBV is an oncogenic g-herpesvirus associated with around 2% of all human cancers such as hematologic and epithelial malignancies [1]. Novel immunotherapeutic options are being developed and tested for treatment of EBV infections and/or EBV-associated malignancies. Immune checkpoint inhibition (ICI) with monoclonal antibodies (mAbs) became a major breakthrough immunotherapy for cancer treatment over the past decade and showed to be effective against several types of tumors. Several mAbs blocking the programmed death receptor protein (PD)-1 or its ligand PD-L1 have been approved or are in clinical development against several types of cancer [3, 4]. The interaction of PD-L1 with PD-1 on inflammatory T cells constitutes one of the major immune escape mechanisms in cHL, associated with development of dysfunctional and tolerogenic T cell responses [5]. In 2017, The U.S Food and Drug Administration granted approval to pembrolizumab (KEYTRUDA®), another PD-1 blocking mAb, for the treatment of adult and pediatric patients with refractory cHL
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
