Viral infections following allogeneic stem cell transplantation: how to cure the cure?

Viral infections are a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation [1]. Transplant patients are susceptible both to primary viral infections and to reactivation of latent viruses, including cytomegalovirus (CMV) and polyomavirus BK (BKV). It is believed that the conditioning regimen, consisting of chemotherapy and radiation, eliminates virus-specific memory T cells, thereby creating a permissive environment for latent viruses to replicate. Subsequently, reactivation of the viruses can occur due to immunosuppressive treatment, given to prevent graft rejection and graft-versus-host disease [2].

The median onset of CMV infection is 40–60 days after transplant in the phase of early immune recovery [3]. Prior to symptomatic CMV disease, most commonly ganciclovir or foscarnet is administered as preemptive therapy to suppress CMV viremia. Although this therapeutic approach is successful in avoiding CMV disease at this stage, it leaves the patient at heightened risk for later infection (more than 100 days after transplant), because it hampers the generation of CMV-specific immunity. Other drawbacks of these antiviral compounds are drug-related toxicity, including nephrotoxicity and myelosuppression, and the risk of inducing resistance. Therefore, immunotherapeutic strategies are now being investigated for their potential to accelerate the reestablishment of antiviral immunity and to decrease the use of antiviral drugs. Concordant with the intracellular nature of viruses, cytotoxic CD8+ T lymphocytes (CTLs) have been shown to be highly important for viral control. For CMV, the coat phosphoprotein 65 (pp65), expressed in all strains of CMV, has been found to be a major target antigen for CMV-specific T cells. CMVpp65-specific CTLs play a critical role in controlling CMV reactivation following allo-HSCT [4,5], and delayed expansion of CMVpp65-specific CTLs may lead to resistant or refractory CMV disease [6]. Moreover, CMV-specific CD4+ helper T cells also play a crucial role in the protection against CMV disease [7–9] and in the generation of memory CD8+ CTLs [10]. Therefore, investigated strategies include the administration of in vitro cultured or ex vivo manipulated CMV-specific CD8+ and/or CD4+ T cells [11,12], preferentially in an early stage following HSCT to let the CMV-specific T cells benefit from the in vivo homeostatic expansion phase. In this way, it is possible to defeat CMV disease, but currently the labor-intensive and time-consuming expansion protocols are being optimized to make this strategy more feasible for clinical use. In addition, more documentation is still needed on how long these T cells will persist in vivo, and whether this strategy is able to prevent late-onset CMV disease and improve overall survival.

Vaccination with CMV DNA or proteins is also under active investigation in patients with allotransplants to generate CMV-specific immunity and to prevent late-onset CMV disease [13]. In addition, dendritic cells (DCs) loaded with CMV-derived antigens are currently being tested as a new and promising vaccination strategy. Dendritic cells, as professional antigen-presenting cells, are able to induce activation of CD8+ and CD4+ T cells specific for the antigens presented by the DC. In a recent study, injection of CMVpp65-pulsed DCs in a allotransplanted patient resulted in induction and expansion of CD4+ and CD8+ CMV-specific T cells, associated with a sustained clearance of CMV viremia [14]. In our laboratory, we use mRNA electroporation to load DCs with CMV antigens for the in vivo activation of CMV-specific T cells in allotransplanted patients. In this way, antigen-presenting cells are not used for in vitro T cell expansion protocols, but are directly administered in vivo, aiming at activating both CD4+ and CD8+ CMV-specific T cells and generating memory T cells [11].

Immunotherapeutic strategies are also worth considering for other viruses causing major serious post-HSCT complications, such as BKV. Although BKV has been found to be an important etiological agent for late-onset hemorrhagic cystitis (HC), until now therapy has been predominantly symptomatic [3], with rather disappointing results when conventional antiviral drugs are used. In order to increase the knowledge relating to BKV-specific cellular immune responses in patients undergoing allo-HSCT, Schneidawind et al. [15] report in this issue of Leukemia and Lymphoma the identification of BKV epitopes in patients with HC following allo-HSCT, detecting BKV peptide VP1 108-specific CD8+ T cell reactivity in five out of seven patients. However, before considering immunotherapy, more research is needed both on BKV-specific CD4+ T cell-mediated immunity and on the correlation between BKV-specific cellular immune responses and the dynamics of BKV replication. It seems that timing of immunotherapy administration will be crucial, in order to enable BKV-specific T cells to prevent reactivation of the virus and not cause more harm by killing BKV-infected uroepithelial cells [2]. Both adoptive transfer of BKV-specific T cells and vaccination have a chance of success, the latter in the case of refractory BKV replication with sufficient T cell recovery following allo-HSCT. When applying the DC vaccination approach as described above for CMV, it would be possible to load DCs with antigens of several latent viruses for the activation of virus-specific CD8+ and CD4+ T cells, aiming at restoring long-lasting cellular immunity.

In conclusion, further investigation of BKV-specific cellular immune responses, as initiated by Schneidawind et al. [15] for patients suffering from HC following allo-HSCT, will provide more insights into the potential for immunotherapy to accelerate virus-specific immune recovery in order to improve the outcome of allotransplanted patients.