Development of multivirus-specific T (VST) cells for the prophylaxis and treatment of viral infections following hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for the treatment of some malignant (i.e., leukemia and lymphoma) and non-malignant hematological diseases (i.e., mutation-related primary immune-deficiencies). Post-HSCT patients are severely immunocompromised and are consequently prone to viral infections, which are a major cause of morbidity and mortality. Viral infections may result from the reactivation of endogenous latent viruses such as cytomegalovirus (CMV) and Epstein-Barr Virus (EBV), or from exogenous agents such as Adenovirus (Adv). Although some drugs are available against CMV infection, they are not effective against EBV or Adv. In addition, their efficacy is limited when there is no concomitant antiviral immune reconstitution. Clonal expansion of cytotoxic T lymphocytes (CTLs) specific for CMV, EBV and Adv (tri-VST) can safely prevent or limit infections with these three most common viruses. There is no doubt regarding the efficacy of HSCT donor-derived virus-specific T (VST) cells in the prophylaxis and the treatment of viral infections associated with HSCT. However, the treatment has not yet become a standard of care post-transplantation in Israel, and only few Centers in the world have successfully implemented this preventive/therapeutic platform as a standard of care for post-HSCT patients. Obstacles to that therapy includes the personalized nature of the treatment, the fact that a VST product can be generated only if the donor cells are HLA-matched and only in the case the donor is seropositive for the virus of interest. Furthermore, the manufacture logistic may delay product availability in the case of early post-transplant infection. In attempt to solve some of these issues, the generation of a third party VST cell bank covering a broad range of HLA-restricted HSCT recipients, sounds to be a particularly attractive option as a high percentage of the BMT candidates at Hadassah Center are originated from consanguineous populations, and therefore share conserved HLA types. We have successfully conducted a pilot experiment in which tri-virus specific CD4+ and CD8+ T cells were specifically enriched in a single culture process, display activation markers (i.e., 4-1BB) and secrete IFN-γ when stimulated with specific viral triggers. We aim to introduce VST cellular products into clinical trials as preventive/standard treatment for post-HSCT viral infections, to extend the VST repertoire to a broad range of post-transplant life-threatening viruses, while shortening the time-consuming manufacturing procedures.

We are confident that once this powerful platform will be robustly implemented, it would significantly improve the patients` resistance to a broad range of viruses, and consequently, increase their chance of survival.