A combination immunosuppressive therapy of cyclosporin A with everolimus may be an effective treatment for pediatric patients undergoing to organ transplants. These are the results of a study recently published in the journal International Immunopharmacology, titled “Effects of mTOR and calcineurin inhibitors combined therapy in Epstein–Barr virus positive and negative Burkitt lymphoma cells”.
Post-transplant lymphoproliferative disorder (PTLD) is a severe complication occurring in patients who receive solid organ transplant and is associated with increased levels of morbidity and mortality. Pediatric patients are at a particularly higher risk than adults. Recent studies have reported an increased incidence of Burkitt lymphoma (an aggressive, rapidly proliferating B-cell lymphoma), which is highly associated with Epstein–Barr virus (EBV) infections in pediatric patients diagnosed with PTLD.
The mammalian target of rapamycin (mTOR) pathway regulates key aspects of cell survival, including cell growth, cell proliferation, and cell motility, and has been previously suggested as an anti-tumor target. Inhibiting mTOR may influence tumor growth, particularly lymphoma’s progression after pediatric transplantation. A new immunosuppressive treatment based on calcineurin inhibitor was also shown to reduce acute rejection and improve survival after solid organ transplantation.
In this study, a team of researchers investigated the effects of combining this immunosuppressive therapy on Burkitt lymphoma cells, treating Epstein–Barr virus positive and negative human Burkitt lymphoma-derived cells with everolimus (an mTOR inhibitor) alone or combined with the immunosuppressive calcineurin inhibitors, tacrolimus or cyclosporin A. The team observed that while treatment with the mTOR inhibitor resulted in a significant reduction in Burkitt lymphoma cell proliferation (and their mitochondria metabolic activity, another parameter analyzed) the combined treatment — everolimus with cyclosporin A — induced an even stronger suppressive phenotype in Epstein–Barr virus negative but not in Epstein–Barr virus positive cells (the in vitro model for BL-PTLD with EBV infection). Combination treatment with the second immunosuppressive calcineurin inhibitor, tacrolimus, completely abolished everolimus’ suppressive effects.
Because there is an increased risk for PTLD in pediatric solid organ transplant recipients, choosing the right immunosuppressive therapy is extremely important. These findings suggest that combining tacrolimus and everolimus is not an efficient immunosuppression therapy in PTLD pediatric patients, because of the competitive effect between the drugs. The calcineurin inhibitor cyclosporin A combined with everolimus is a preferred therapy, although additional studies (particularly in vivo) are required to confirm these preliminary findings.