CMV Specific T Cell Therapy After Allogeneic Stem Cell Transplantation.

Plain-language summary

Viral infections remain an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), especially after myelo-ablative conditioning and if the donor is antigen-mismatched or haplo-identical.. In the described setting the patient's own immune system has been destroyed by the necessary highly immuno- and myelo-ablative conditioning and all memory against infections has been deleted. Therefore, there is a high risk for several viral infections and other infectious organisms.Both primary viral infections and reactivations can occur, and patients can become refractory to antiviral treatments, or in some cases an adequate antiviral treatment is unavailable or too toxic. In this study, the investigators will target CMV, as refractory CMV infection and disease is accompanied by an extremely high mortality rate and therefore the development of new treatment approaches is required. Despite the available antiviral drugs, a considerable number of patients are facing an insufficient control of CMV reactivation after SCT. Because reconstitution of CMV-specific T cells confer protection against the development of CMV disease after SCT, attempts have been made to restore antiviral immunity by direct infusion of CMV-specific T cells. Most clinical cellular immunotherapy protocols for CMV treatment have used CMV-specific cytotoxic CD8+ T-cell lines generated by repetitive in vitro stimulation with CMV antigens with success. Despite the proven efficacy, use of cellular therapy in the clinic has been limited, because the approach is time and labor consuming and requires specialized facility allowing handling of the therapeutic cells according to good manufacturing practice. In addition, no sustained response was seen after adoptive transfer that involved only cytotoxic CD8+ T cells. This phenomenon is supported by the fact that recall responses to latent infections depend on the presence of CD4+ T cells to help cytotoxic CD8+ T cells. An alternative approach for the transfer of T-cell immunity is the isolation of Ag-specific T cells ex vivo from the blood of CMV seropositive donors, based on interferon γ (IFN-γ) secretion of T cells after in vitro stimulation with viral Ag, resulting in a combination of CD4+ T helper and cytotoxic CD8+ CMV specific T cells. Using this strategy, a short-term ex vivo protocol was developed for the isolation of pp65 (CMV immunodominant protein)-specific T cells. Since then, several centers have used this protocol in the clinic, infusing low numbers of pp65-specific T cells, that were able to restore protective T-cell immunity against CMV in a post SCT setting in patients with refractory CMV disease or viremia. For this protocol the investigators have set up and validated this method of CMV-specific T-cell generation in the Ghent University Hospital and the investigators will make it available for other Belgian transplant centers.

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