Research Highlights.

Normothermic Machine Perfusion Versus Static Cold Storage in Donation After Circulatory Death Kidney Transplantation: A Randomized Controlled Trial Hosgood SA, Callaghan CJ, Wilson CH, et al. Nat Med. 2023. Addressing the donor organ shortage remains a key challenge in the field, and therefore optimizing organ quality after donation after circulatory death (DCD) is crucial. However, DCD kidneys exhibit higher vulnerability towards standard preservation techniques with static cold storage (SCS), leading to greater occurrence of delayed graft function (DGF) and thereby worsening of transplant outcomes. To address these consequences, normothermic machine perfusion (NMP) is gaining traction as a novel auxiliary preservation strategy.1 Despite robust evidence of clinical benefit in liver allografts,2 only sparse data have so far become available for kidney transplantation. In a recent study from Hosgood and coworkers,3 new high-quality insights are attained through a randomized controlled trial of 338 DCD kidney grafts undergoing SCS with or without 1 h of NMP before transplant. Following exclusions, 277 cases were assessed via intention-to-treat analysis with the primary endpoint of DGF necessitating dialysis within 1 wk post-surgery. DGF rates between treatment groups did not differ significantly, amounting to 58.5% on SCS alone and 60.7% with SCS in combination with 1-h NMP. Post hoc subgroup analyses further revealed no statistically meaningful difference for pre-dialysis patients or for kidneys exposed to a second period of cold ischemia because of operating room logistics. In patients who were on dialysis before transplant, however, the creatinine reduction rate on day 2 post-transplant was significantly higher with an additional 1-h NMP treatment. Moreover, no increase of adverse events was found in the NMP group, including biopsy-proven acute rejection, renal vessel thrombosis, and infection. In conclusion, this important trial found that a 1-h application of NMP following SCS in DCD kidneys is safe and feasible. However, NMP did not reduce DGF rates compared with SCS alone. This outcome may challenge early hopes for rapid clinical translation, yet builds a solid scientific foundation for ensuing investigations that will identify the optimal use case for NMP in kidney allograft preservation. Future trials may consider extending perfusion times to facilitate repair.4 Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant Prockop SE, Hasan A, Doubrovina E, et al. JCI. 2023;133:e165476. In hematopoietic stem cell transplant (HCT) recipients, cytomegalovirus (CMV) reactivation poses a substantial risk. Previous work has shown promising results with adoptive transfer of donor-derived CMV-specific CD8+ cytotoxic T lymphocytes to target infected cells,1 but this comes at a significant logistical and financial cost. Banked third-party CMV-specific T cells from healthy individuals present an exciting alternative, as studies targeting EBV with this strategy have already demonstrated.2 In this study, Prockop and coworkers3 present comprehensive toxicity and efficacy results from a phase I/II trial with adoptive transfer of third-party CMVpp65-sensitized T cells (CMVpp65-VSTs) in 67 patients with CMV viremia or disease following HCT. Only patients refractory to antiviral induction therapy with ganciclovir, foscarnet, or cidofovir for at least 2 wk were eligible. Additionally, the CMVpp65-VSTs shared a minimum of 2 HLA alleles with the recipient. Moreover, these cells were HLA-restricted by an allele shared by the recipient and the HCT donor. Adoptive cell transfer was administered intravenously in 35-d cycles, each starting with the first of 3 weekly infusions of 1 × 106 CMVpp65-VSTs/kg/dose. Adverse effects were infrequent; of 9 patients with 21 possibly related adverse events, none were clearly related to CMVpp65-VST-infusion. Notably, 6 cases of adverse respiratory effects could have arisen from augmented local effects of the CMVpp65-VSTs in CMV-infected lung tissue because 2 affected patients had documented CMV pneumonia before adoptive cell transfer. However, 10 further patients also had documented CMV pneumonia or infiltrates concerning for CMV pneumonia and did not exhibit similar adverse respiratory effects. Overall, there were no safety concerns due to CMVpp65-VST-infusion. CMVpp65-VST treatment displayed clear efficacy, with a complete response (full viremia clearance and biopsy-proven resolution of invasive disease) in 20 patients, and durable partial response (2log10, ie, 100-fold, decrease in CMV viral load and resolution of disease-related clinical symptoms) in 18 patients. Together, these results represent a response in 64.4% of treated patients. CMV-related death occurred in only 1 of 38 responders and 8 of 21 nonresponders, with a 6-mo overall survival of 79% and 29%, respectively. Further analyses revealed important risk factors for nonresponse, including T-cell–depleted grafts; low recipient CD3+, CD4+, and CD8+ T cell levels before therapy; prior ganciclovir treatment (as opposed to other antiviral regimens); and HLA-B35 restriction of CMVpp65-VSTs, which possibly impaired epitope presentation. Notably, CMVpp65-specific T cells from both the HCT donor and recipient were found to play a part in evoking favorable responses, even in cases of CMV-seronegative HCT donors with no detectable CMV-specific T cells before third-party cell therapy. The authors interpret this as an indicator for recruitment of engrafted donor or residual host CMV-specific T cells, which may also explain long-term persistence of (partial) responses despite the disappearance of CMVpp65-VSTs within 8 wk post-infusion. Allogeneic cellular therapies are of substantial interest. They have the potential for “off the shelf” treatment, eliminating the complexities of autologous production. This study provides further evidence for the feasibility of this approach, with hugely encouraging findings in the treatment of challenging refractory infections in high-risk patients.