Understanding risk and enhancing safety in immunotherapy trials.

In the past decade, there has been major progress in the development of novel immunosuppressive therapies. In addition, there have been advances in the clinical applications of these therapies to suppress both alloimmunity and autoimmunity. In some situations, however, the toxicity of the therapies, including infections, can limit their use. In this issue of Clinical Infectious Diseases, Loechelt and colleagues performed monitoring for herpesviruses in 126 patients with type 1 diabetes mellitus (DM) [1]. These patients were enrolled in a randomized controlled trial of daclizumab and mycophenolate mofetil (MMF). The original trial did not find a significant protective effect of daclizumab and MMF on the loss of insulin-producing β cells in patients with new-onset type 1 diabetes [2]; Loechelt et al concluded that daclizumab and MMF did not increase morbidity from herpesviruses. Nevertheless, the monitoring of these patients for herpesvirus infections has provided novel insights into the effects of common viral infections with the use of potent exogenous immunosuppression in the nontransplant setting. In the current study, the authors performed careful laboratory and clinical monitoring for Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV). Both primary infections and reactivations were observed but significantly increased morbidity was not seen in patients receiving either one or both immunosuppressive drugs compared with placebo. There was a trend toward greater EBV viral burden (P = .06) in patients receiving both daclizumab and MMF compared to those on no immunosuppression. However, most patients were either asymptomatic or had a self-limited mononucleosis-like syndrome. EBV is an important herpesvirus in transplantation; pediatric transplant patients especially are at greater risk of posttransplant lymphoproliferative disease (PTLD), primarily because they are often EBV-seronegative prior to transplantation and may receive a seropositive organ. In this study, EBV viral loads were reportedly not significantly different from viral loads measured in transplant patients at the same lab. In the transplant setting, high EBV viral loads have been correlated with an increased risk of PTLD [3]; however, other than mononucleosis-like syndrome in 3 patients, there was no development of lymphoproliferative disease in the current study. This may have been due partly to the discontinuation of immunosuppression when 2 sequential positive viral loads were obtained. Viral load monitoring and subsequent reduction of immunosuppression has been shown to decrease progression to PTLD in the transplant setting [4]. In contrast to the transplant setting, the subjects in Loechelt et al’s study were also on fewer immunosuppressive agents than would typically be used and had not received a T-cell–depleting agent such as antilymphocyte globulin (a known risk factor for PTLD) [5]. Transplanted patients are often also on immunosuppressive regimens that include a calcineurin inhibitor and/or corticosteroids, in addition to MMF. There are various other contrasts between the type 1 DM setting and transplant setting. In a seronegative individual who has undergone transplant, there is an allogeneic stimulus and transfer of cells harboring latent virus (if the donor is seropositive). Also, ischemic injury to the graft and major histocompatibility complex mismatch could all promote local viral replication, Received 17 September 2012; accepted 24 September 2012; electronically published 5 October 2012. Correspondence: Atul Humar, MD, MSc, FRCPC, Alberta Transplant Institute, 6-030 Katz Center for Health Research, University of Alberta, Edmonton, AB, Canada T6G 2E1 ([email protected]). Clinical Infectious Diseases 2013;56(2):255–7 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/cis855