Dual monoclonal antibody therapy for the treatment of PTLD?

Post-transplant lymphoproliferative disorder (PTLD) is a major complication of solid organ transplantation (1, 2). Associated with a high degree of morbidity and mortality, this unusual entity is seen after all types of solid organ transplants, although more so in thoracic organ and intestinal transplants (3, 4). Other risk factors for PTLD include the seromismatch between donor and recipient to viruses such as Epstein–Barr virus (EBV) and cytomegalovirus (CMV), the age and race of the recipient, and intensity of immunosuppression (5–8). It is currently believed that PTLD arises as a result of Epstein–Barr virus infection and transformation of B cells in the setting of post-transplant immunosuppression (9). In otherwise immunocompetent hosts, the infected B cells would be inhibited from proliferating by CD8+ lineage host T cells. Unfortunately, current immunosuppressive agents lack selectivity for different T-cell lineages, thus leading to ineffective inhibition of the infected B cells in the transplant recipient. In addition to the complexities of pathogenesis, PTLD presents several therapeutic challenges. The optimal treatment strategies for PTLD are not known. The current recommended practice is to reduce immunosuppression in mild cases (10). More severe cases are treated with one of several options, including a-interferon, anti-B-cell antibodies such as anti-CD 20, or Non-Hodgkin’s lymphoma chemotherapy (11–13). Anti-CD 20 (Rituximab ; IDEC Pharmaceuticals Corp, San Diego, CA, USA) therapy is of particular interest since this mAb binds to the CD20 antigen that is expressed specifically on normal and infected B cells, but is not expressed on other immune cells. In comparison with chemotherapy and a-interferon, anti-CD 20 therapy is thus less likely to inhibit other components of the immune system. There are now multiple reports of the successful use of anti-CD 20 therapy to treat PTLD (11, 14, 15). However, all these treatment options possess their own toxicities and there is the additional risk of graft rejection or graft loss. In situations where the function of the organ cannot be easily replaced by medical means (as is typically the case in heart and liver transplants), the loss of the graft function is potentially fatal (16). Indeed, the use of Rituximab therapy in patients with PTLD following liver transplantation has been associated with subsequent lethal chronic graft rejection, despite successful resolution of the PTLD (17). In the series of PTLD patients treated with anti-CD 20 mAb by Serinet et al., three patients developed severe acute (and subsequently fatal chronic) rejection shortly after the resolution of the PTLD, at a time when minimal or no immunosuppression was being utilized (17). This report highlights yet another therapeutic challenge in treating PTLD, i.e. the dilemma regarding the optimal time to re-initiate full immunosuppression and the type of agent to use. Restarting full immunosuppression after treating the PTLD runs the risk of repeat viral infections which may be life-threatening. Delaying the restoration of full immmunosuppression may lead to acute rejection episodes, which in some situations may also be life-threatening. In addition, non-specific immunosuppressive agents such as cyclosporine or tacrolimus are themselves associated with the development of PTLD and thus may not be ideal agents to use immediately after successful PTLD therapy. In this issue of Pediatric Transplantation, Venzke et al. have suggested a possible solution to the dilemma. They describe a novel dual and sequential monoclonal antibody therapy approach for treating PTLD in a pediatric liver transplant recipient, opting to use a more selective agent basiliximab as monotherapy immunsuppression once their patient responded to anti-CD 20 therapy (18). Basiliximab (Simulect ; Novartis Pharmaceuticals, East Hanover, NJ, USA) is a human–mouse chimeric monoclonal anti-IL-2 receptor antibody that can occupy and block signaling through the a-subunit of the IL-2 receptor Pediatr Transplantation 2003: 7: 337–338