Epstein Barr Virus: Development of Vaccines and Immune Cell Therapy for EBV-Associated Diseases.

Xinle Cui,Clifford M Snapper

doi:10.3389/fimmu.2021.734471

Abstract

Epstein-Barr virus (EBV) is the first human tumor virus discovered and is strongly implicated in the etiology of multiple lymphoid and epithelial cancers. Each year EBV associated cancers account for over 200,000 new cases of cancer and cause 150,000 deaths world-wide. EBV is also the primary cause of infectious mononucleosis, and up to 70% of adolescents and young adults in developed countries suffer from infectious mononucleosis. In addition, EBV has been shown to play a critical role in the pathogenesis of multiple sclerosis. An EBV prophylactic vaccine that induces neutralizing antibodies holds great promise for prevention of EBV associated diseases. EBV envelope proteins including gH/gL, gB and gp350 play key roles in EBV entry and infection of target cells, and neutralizing antibodies elicited by each of these proteins have shown to prevent EBV infection of target cells and markedly decrease EBV titers in the peripheral blood of humanized mice challenged with lethal dose EBV. Recent studies demonstrated that immunization with the combination of gH/gL, gB and/or gp350 induced markedly increased synergistic EBV neutralizing activity compared to immunization with individual proteins. As previous clinical trials focused on gp350 alone were partially successful, the inclusion of gH/gL and gB in a vaccine formulation with gp350 represents a promising approach of EBV prophylactic vaccine development. Therapeutic EBV vaccines have also been tested clinically with encouraging results. Immunization with various vaccine platforms expressing the EBV latent proteins EBNA1, LMP1, and/or LMP2 promoted specific CD4+ and CD8+ cytotoxic responses with anti-tumor activity. The addition of EBV envelope proteins gH/gL, gB and gp350 has the potential to increase the efficacy of a therapeutic EBV vaccine. The immune system plays a critical role in the control of tumors, and immune cell therapy has emerged as a promising treatment of cancers. Adoptive T-cell therapy has been successfully used in the prevention and treatment of post-transplant lymphoproliferative disorder. Chimeric antigen receptor T cell therapy and T cell receptor engineered T cell therapy targeting EBV latent proteins LMP1, LMP2 and/or EBNA1 have been in development, with the goal to increase the specificity and efficacy of treatment of EBV associated cancers.

Highlights

Epstein-Barr virus (EBV) is a gamma human herpesvirus that primarily infects B cells and epithelial cells
Patients undergoing solid organ or stem cell transplantation are at risk of developing uncontrolled B cell proliferation due to EBV reactivation, termed post-transplant lymphoproliferative disorder (PTLD) that can evolve into Hodgkin lymphoma or non-Hodgkin lymphoma, and a similar phenomenon occurs in patients with AIDS [3, 12,13,14]
EBV infects more than 95% of the human population, causes infectious mononucleosis (IM) in 70% of adolescents and young adults in developed countries, accounts for 1.5% of all cancers worldwide and represent 1.8% of all cancer deaths

Summary

INTRODUCTION

Epstein-Barr virus (EBV) is a gamma human herpesvirus that primarily infects B cells and epithelial cells. Though the role of EBV in HL pathogenesis is still not fully understood, it is reported that all EBV-positive tumors consistently exhibit Latency II infection with high levels of the LMP1 and LMP2A proteins maintained in every Reed-Sternberg cell [41]. PTLD display Latency III infection, and all the eight EBV latent antigens are expressed, including six EBV nuclear antigens EBNA 1, EBNA2, EBNA3A, EBNA3B, EBNA 3C, EBNA 6/LP and two latent membrane proteins LMP1 and LMP2 [41, 42] These latent EBV proteins play key roles in the uncontrolled proliferation of B cells, and they are the targets of EBV specific CD8+ T cells [21, 123]. This was confirmed by the recently published study by Bu et al that EBV gH/gL or gH/

Results

Adoptive T-cell therapy Donor-derived EBV-specific T lymphocytes

CONCLUSION