Trials In Transplant Recipients Research Articles

Phenotypic and functional characterization of posoleucel, a multivirus-specific T cell therapy for the treatment and prevention of viral infections in immunocompromised patients

BackgroundDeficits in T cell immunity translate into increased risk of severe viral infection in recipients of solid organ and hematopoietic cell transplants. Thus, therapeutic strategies that employ the adoptive transfer of virus-specific T cells are being clinically investigated to treat and prevent viral diseases in these highly immunocompromised patients. Posoleucel is an off-the-shelf multivirus-specific T cell investigational product for the treatment and prevention of infections due to adenovirus, BK virus, cytomegalovirus, Epstein–Barr virus, human herpesvirus 6 or JC virus. MethodsHerein we perform extensive characterization of the phenotype and functional profile of posoleucel to illustrate the cellular properties that may contribute to its in vivo activity. Results and ConclusionsOur results demonstrate that posoleucel is enriched for central and effector memory CD4+ and CD8+ T cells with specificity for posoleucel target viruses and expressing a broad repertoire of T cell receptors. Antigen-driven upregulation of cell-surface molecules and production of cytokine and effector molecules indicative of proliferation, co-stimulation, and cytolytic potential demonstrate the specificity of posoleucel and its potential to mount a broad, polyfunctional, and effective Th1-polarized antiviral response upon viral exposure. We also show the low risk for off-target and nonspecific effects as evidenced by the enrichment of posoleucel in memory T cells, low frequency of naive T cells, and lack of demonstrated alloreactivity in vitro. The efficacy of posoleucel is being explored in four placebo-controlled clinical trials in transplant recipients to treat and prevent viral infections (NCT05179057, NCT05305040, NCT04390113, NCT04605484).

The role of mesenchymal stromal cells in chronic transplant rejection after solid organ transplantation

Despite impressive improvements in short-term survival after solid organ transplantation (SOT), the long-term outcome remains an important challenge. In recent years, it has become evident that ongoing alloreactivity, cellular and/or humoral, may play a critical role in the premature loss of kidney allografts. Clinical trials with mesenchymal stromal cells (MSCs) are currently underway for the treatment of various inflammatory disorders. Due to their immunosuppressive and reparative properties MSC immunotherapy constitutes an attractive intervention for chronic rejection, while avoiding the undesired adverse effects associated with excessive use of immunosuppressive drugs. The immunoregulatory properties of MSCs in both cellular and antibody-mediated inflammatory models and diseases have highlighted their potential to treat chronic rejection after SOT. Moreover, MSCs can also induce tissue regeneration and repair due to their antifibrotic and angiogeneic properties. Studies in experimental animals after SOT support the potential for MSCs to treat or prevent ongoing alloreactivity and the first clinical trials in transplant recipients are underway. MSCs are arising as promising cellular immunotherapy in transplant recipients and carry the potential to prevent or reduce the consequences of chronic or ongoing alloimmune injury.

Reducing the Risk of Left Ventricular Hypertrophy in Kidney Transplant Recipients: The Potential Role of Mammalian Target of Rapamycin

Persistence of left ventricular hypertrophy (LVH) following renal transplantation is associated with unfavorable outcomes in renal transplant recipients. This review presents clinical data on LVH after renal transplantation and the role of antihypertensive therapy, especially ACE inhibitors, to reduce left ventricular mass, as well as the effects of interactions between antihypertensive medications acting on the renin–angiotensin system and immunosuppressive agents to regress LVH among renal transplant recipients. The effectiveness of sirolimus (SRL) to reduce posttransplantation LVH is also discussed in light of both animal model studies and 2 clinical trials in transplant recipients that showed the efficacy of this immunosuppressive agent to treat LVH in both kidney and heart transplant recipients.

Therapeutic monitoring of tacrolimus.

The expanding repertoire of novel, low molecular weight immunosuppressive agents currently undergoing clinical trials in transplant recipients and patients with autoimmune disease offers great promise for the more selective control of the immune response in these populations.' Cyclosporin was the first of these new agents, and was introduced into clinical practice during the early 1980s. In common with cyclosporin, all of the recently developed drugs have been designed to suppress the immune system more specifically than former regimens based on T cell depletion, steroids and azathioprine. However, none is without side-effects, and increasingly large and complex controlled trials are needed to establish the relative clinical merits of these new drugs when compared, or used in combination, with established cyclosporin-based immunosuppression. After extensive multicentre clinical trials in both Europe? and the USA,' the second of these new agents, tacrolimus (FK506), was granted a licence in the UK in June 1994, for use in liver and kidney transplant recipients, for both primary immunosuppression and the treatment of allograft rejection resistant to conventional therapy.