Immunotherapy

Although Epstein-Barr virus is associated with a number of malignant and non-malignant diseases, EBV infection cannot effectively be treated or prevented in the clinic. Antiviral drugs that inhibit virus replication in vitro are rather ineffective in patients. Therefore, novel drug targets are evaluated to develop more efficacious therapeutics that target the maintenance of EBV infection and EBV-induced cell proliferation and transformation.

The treatment of EBV-associated malignancies is still clinically challenging. EBV-positive Burkitt's and Hodgkin's lymphoma usually respond well to chemo/radiotherapy. However, other EBV-associated tumors such as nasopharyngeal carcinomas or post-transplantation B-cell lymphoproliferative disorders (PTLD) are often difficult to manage.

However, PTLD has been successfully treated or prevented in clinical research studies by the infusion of EBV-specific T cells. The same is true for another human herpesvirus, cytomegalovirus, which also causes severe disease after transplantation.

For a better understanding of the interaction of these viruses with their host and of the therapeutic principle of specific T cell transfer, we are studying the nature of the virus-specific T cell response and the antigenic repertoires of  specific T cells that recognize EBV and other herpesviruses such as cytomegalovirus and human herpesvirus 6. We investigate how, when and where viral antigens are processed in the infected cell for their presentation to antigen-specific T cells, and which of the many viral antigens represent the important targets of control by T cells. The study of the mechanisms of antigen presentation will also help identify new targets of pharmacological intervention. 

Although virus-specific T cell transfer has proven remarkably safe and efficient, it has never entered routine clinical practice, mainly because of problems of infrastructure and legal regulation. Specific T cell transfer is a highly personalized procedure and requires specialized laboratories to prepare and analyze the specific T cells. Therefore, we are developing more simplified and generally applicable procedures to generate virus-specific T cells for therapy, such as stimulation with virus-like particles and with multiepitope peptide pools. We hope to facilitate future routine clinical application of virus-specific T cells.

In a complementary approach, we pursue the development of an EBV vaccine. It could prevent infectious mononucleosis, also called Pfeiffer's glandular fever, which is a transient but debilitating disease that affects many adolescents and young adults after their first infection with EBV, and increases the likelihood of EBV-associated cancer later in life. An EBV vaccine may also be of great benefit if applied in patients who are scheduled for organ transplantation and still EBV-negative. Such a vaccine is likely to prevent EBV reactivation and disease after receiving a transplant from an EBV-positive donor.

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