While CNIs make up an essential component of current IS regimens, their use is frequently associated with acute and chronic renal impairment, post-transplant diabetes, hypertension, and dyslipidemia (16). The key strategy in minimizing this nephrotoxicity is to reduce CNI exposure to the minimal effective dosage. The use of mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, or co-stimulation blockade with belatacept, can facilitate the reduction or withdrawal of CNI use, but is constrained by a delicate risk-benefit ratio and has not been examined in all organ types (17–20).

There is also a well-established link between IS and oncogenesis. Hanahan and Weinberg’s work classifying the hallmarks of cancer considers immune surveillance critical to identifying and destroying burgeoning tumors (21). Although this link may mean IS imposes a high risk of tumor development, the reality may not be so simple due to the complexity of the immune system and the possibility that it has dichotomous roles in both antagonizing and enhancing tumor development and progression (21).

Furthermore, IS treatments reduce the body’s defenses against opportunistic pathogens; this results in a burden of infective complications even in otherwise successful transplantations (20). Common infections include, but are not limited to, cytomegalovirus (CMV), Pneumocystis jirovecii, herpes simplex virus, BK virus, and Mycobacterium tuberculosis complex. With an increase in the number of infections produced by multi-drug resistant bacteria, these risks are only set to increase (20, 22).

While the use of standard IS minimizes the risk of acute or chronic graft failure and has been shown to reduce mortality among transplant patients, effective strategies to minimize these side effects remain a key unmet medical need for patients undergoing SOT (8, 23).

Extracorporeal photopheresis (ECP) is a leukapheresis-based therapy approved for the treatment of disorders with T-cell involvement, including cutaneous T-cell lymphoma, autoimmune diseases, and graft versus host disease (GvHD) following hematopoietic stem cell transplantation (HSCT) (24, 25). There is also evidence that ECP can be used as prophylaxis or treatment for solid organ allograft rejection (25–27), and it has shown potential as an IS-modifying therapy for patients undergoing SOT (24, 27).

The ECP procedure can be performed using a single integrated system (24). During treatment, the integrated system collects whole blood from the patient and separates leukocytes from plasma and non-nucleated cells. The leukocytes are then treated with a photosensitizing agent (8-methoxypsoralen) and exposed to ultraviolet-A (UVA) irradiation, before reinfusion (24, 25). After treatment, a large proportion of leukocytes undergo apoptosis, and subsequently phagocytosis by immature dendritic cells, promoting immunomodulatory effects (25, 28). The exact mechanisms of action by which ECP mediates its effects have not been fully characterized; however it is hypothesized that ECP works through a combination of dendritic cell initiation, modification of cytokine profiles and stimulation of T-cells (25). Generally, these activities start with the induction of apoptosis and simultaneous physiological activation of monocytes. These activated monocytes are presented to apoptotic lymphocytes and phagocytosed and, in the case of cancerous cells, leads to improved anti-tumor immunity (29–33). Additionally, and most relevant here, the immune tolerance aspects of the ECP mechanism of action are thought to be mainly actioned through Treg cell production and stimulation of anti-inflammatory cytokines (e.g. IL-10 and TGF-β) (25, 29, 34). These multiple effects of ECP, including anti-tumor immunity, inhibition of inflammation vis immune tolerance and modulation of genes involved in cell adhesion and diapedesis, work to restore healthy immune function by immune modulation (29–33); as such, it is important to note that, unlike conventional immunosuppressive therapies, ECP promotes regulatory T-cell production without inducing global IS (24, 26, 28).

The aim of this review is to discuss the IS-modifying effects of ECP in the field of SOT, with evidence from heart, lung, kidney, and liver transplantation, and the potential of ECP to augment conventional IS regiments in post-SOT patients.

Cardiac allograft rejection is the major cause of morbidity and mortality in the first three years following heart transplantation (38), with acute rejection (AR) occurring in approximately 13% of patients within the first year (51). This explains the necessity of IS, however opportunistic infections, nephrotoxicity, neurotoxicity, and secondary malignancies have been linked to the use of standard IS in heart transplant recipients (38).

ECP has been used successfully to promote a more tolerogenic state in transplant patients and to modify the dosage of standard IS required by heart transplant recipients (27). The British Photodermatology Group (BPG), the UK Cutaneous Lymphoma Group (UKCLG; formerly the UK Skin Group) and published guidelines from the American Society for Apheresis (ASFA) support the use of ECP as a treatment for cardiac allograft rejection and rejection prophylaxis (26, 52, 53). The International Society for Heart and Lung Transplantation (ISHLT) also recommends ECP for the treatment of chronic or resistant acute cellular rejection (53–55).

A key threat to long-term survival and HRQoL following lung transplantation is chronic lung allograft dysfunction (CLAD). The most common CLAD phenotype is bronchiolitis obliterans syndrome (BOS) (27). Initial treatment of BOS may include augmentation of standard IS regimens, such as high-dose pulses of CS (while avoiding sustained administration of CS) and switching CNIs and drug classes (including the use of mTOR inhibitors) (58). Subsequent salvage therapy for those with unresponsive BOS includes ATG, and less frequently total lymphoid irradiation, OKT3, alemtuzumab, methotrexate, and cyclophosphamide (55). In selected cases, surgical treatment of gastroesophageal reflux disease may be considered. In most cases, this approach of modifying standard IS regimens seems to only stabilize or slow BOS progression, rather than show reversal of the process or normalization of graft function (27, 41). Thus, there is a need for more effective treatment options.

The ASFA published guidelines suggest ECP may be an appropriate treatment of lung transplant rejection, especially for those with early BOS (27, 59). The European Dermatology Forum indicated that ECP has been used in lung transplant recipients with a low rate of side effects, and that it can stabilize lung function in patients with CLAD/BOS (53).

Overall, ECP has shown promise in patients with acute recurrent cellular rejection and BOS, but there is a need for prospective RCTs in this specific field. While there are no guidelines or recommendations for early prophylactic use of ECP in lung transplantation, this indication is currently under investigation (53).

Case studies currently comprise the majority of available published evidence on the use of ECP in kidney transplantation, and only a small subset of these report IS-modifying outcomes related to the use of ECP (Table 1) (27). There is, however, a particularly high unmet need in kidney transplantation with no standard of care for chronic active rejection (62, 63). There are also no guidelines currently available for use of ECP in kidney transplantation.

One of the earliest case reports of ECP for treatment of recurrent rejection was published by Dall’Amico et al. (1998) and reports IS-modifying outcomes in renal transplant recipients (45). Of the four patients included in this study, ECP permitted a reduction of steroid use in three (mean ± SD; dosage pre-ECP: 16 ± 11 mg; dosage 6 months post-ECP: 8.5 ± 1 mg). Cyclosporine A and azathioprine doses were maintained during ECP treatment. Additionally, ECP was associated with improvement in glomerular filtration rate (GFR) in three ECP-treated patients and stabilization in the fourth patient.

Jardine et al. (2009) report a ten patient prospective case series where ECP was used to treat recurrent rejection and was associated with resolved rejection in all cases (12). Additionally, ECP enabled a reduction in overall immunosuppressive load with the dose for standard IS reduced following ECP initiation (Table 2). This reduction included both a reduced steroid pulse dose (mean; pre-ECP dose: 4.78 g/patient; post-ECP dose: 0.38 g/patient; n=10) and fewer days on antilymphocyte therapy (mean; pre-ECP: 15.4 days; post-ECP: 0.0 days; n=10).

Kumlien et al. (2005) reported the outcomes of seven patients with acute refractory renal graft rejection treated with ECP following lack of response to conventional antirejection treatment (46). At final follow-up (9–43 months) all patients had functioning grafts and five saw improvement in renal function, while in the remaining two patients renal function stabilized.

A multi-center retrospective study by Tamain et al. (2019) included 33 kidney transplantation recipients, one of the largest sample sizes investigating ECP in adult kidney transplant recipients (47). While modifications to standard immunosuppressive therapies were not specific outcomes included in this study, the indications for ECP use in kidney allograft rejections included patients that were resistant to standard therapies (n=18) or those for whom standard therapies were contraindicated due to active infections or cancers (n=15). Five patients in the study were treated by ECP as a single therapy, with all five still having a functional graft at 12 months. Outcomes beyond 12 months were more variable, with functional grafts at 24 months (n=2) and 72 months (n=1); one patient died with a functional graft at 22 months and the final patient did not recover their kidney function. The other 28 patients received ECP therapy along with standard IS treatments. Of all ECP-treated patients, 20 (61%) had a functional graft and 11 (33%) had a stabilization of kidney function at 12 months following ECP initiation. The study noted some efficacy limitations in certain patient groups, such as those with poor renal function at treatment initiation or those with long delays between rejection and treatment initiation; however, this is consistent with limitations of other standard IS therapies.

Augusto et al. (2021) presented three case studies on the use of ECP to treat AR in kidney transplant patients who had reduced standard IS following PTLD diagnosis, measuring kidney function, donor-specific antibody (DSA), and graft histology (48). The first patient started ECP three months after developing PTLD, yet had to stop after 16 sessions because of vascular access failure; however, complete AR resolution was still achieved. The other two patients were both initially treated with rituximab, amongst other IS therapies, following development of Epstein-Barr virus (EBV)-induced PTLD. Extracorporeal photopheresis was then introduced to the treatment regimen after persistence of AR. Both patients experienced favorable long-term follow-up with stable kidney function, undetectable DSA and no PTLD recurrence. ECP was found to be beneficial for controlling AR in all cases with favorable outcomes in all three patients. Initial observations indicated that ECP treatment should be initiated during the early stages of rejection.

In a case series of four kidney transplant patients, all of whom were considered as high immunological risk recipients due to previous transplantation or calculated PRA I +II levels of >50%, three patients presented stabilization of renal function during ECP treatment (64). In the fourth patient, no improvement was observed following ECP treatment and the patient experienced a progression to kidney graft failure. In two cases where patients had concomitant infections preventing administration of standard IS therapy, ECP was introduced alongside other therapeutic measures, enabling reduction of IS as well as stabilization of renal function. However, in one of these patients, treatment had to be subsequently suspended for logistical reasons and graft function worsened again.

Liver transplantation is a well-established intervention for patients with irreversible liver failure or liver cancer, however the potential benefit of transplantation may vary depending on the cause (65). Although survival following liver transplantation has improved over time, late graft loss due to disease recurrence or chronic rejection can occur, with rates of loss varying due to etiology and post-transplant recidivism due to alcohol abuse (65).

While standard IS appears to be a successful management strategy in liver transplant recipients, a possible IS-modifying role of ECP has been investigated. A prospective single-center study was conducted in Italy in patients perceived to be at high risk of renal and neurological complications (49). The study investigated the use of ECP to avoid CNIs during the early post-operative treatment course. A full CNI-modifying regimen was possible in 5.5% of ECP-treated patients, while 33.3% were able to delay CNI by >8 days and 61.2% by ≤8 days as compared with controls. ECP was well tolerated by all treated patients, with no major side effects observed. Additionally, ECP did not appear to increase the risk of infectious complications, therefore sparing patients from antiviral and/or antibacterial prophylaxis. Overall, there was a statistically significant higher rate of survival in the ECP-treated group; 1-, 6-, and 12-month Kaplan-Meier estimates of patient survival were 94.4%, 88.1%, and 88.1% in the ECP group as compared with 94.4%, 77.7%, and 72.2% in the control group (P<0.0001).

A series of studies have investigated the use of ECP following liver transplantation using three protocols; the ‘avoiding CNI protocol’, the ‘ABO-incompatible protocol’, and the ‘hepatitis C virus (HCV)-positive protocol’ (66). Investigation into the HCV protocol was subsequently paused due to the introduction of direct antiviral drugs, however, preliminary data from the other two protocols support the theory that ECP can provide immunomodulation with low complication rates in terms of both survival and quality of life (67). The ‘avoiding CNI protocol’, introduces ECP as an alternative form of IS in the immediate post-operative period in an attempt to reduce CNI-related mortality. While this study provided preliminary data on potential areas for the use of ECP for immunomodulation, these results require further consideration. The ABO-incompatible protocol’ was developed for use in patients who rapidly deteriorate due to hepatic failure. At the final follow up of the preliminary trial (mean follow-up: 2836 days [range: 706–4335]), none of the 12 patients receiving ECP had developed an acute rejection (67).

This review presents a comprehensive overview of studies on IS-modifying properties of ECP across organ types across several decades of research.

A key limitation of this field is the lack of evidence provided by RCTs; it is challenging to draw generalized conclusions from the limited data available. The studies discussed in this review include case reports, case series and non-randomized cohort studies, and represent a maximum evidence level of three according to the Oxford Centre for Evidence-Based Medicine criteria (50). Finally, while available data support ECP for IS modification in kidney transplantation (47), there are limited published data on its use, safety, and efficacy in this indication. There is a clear need for further research in this area to support evidence-based decision-making, particularly in the context of kidney and liver transplantation.