Balancing Rejection and Remission: Immune Checkpoint Inhibitors in Solid Organ Transplant

Solid organ transplant (SOT) remains a well-established modality to improve overall survival (OS) and quality of life in those with terminal organ failure. However, SOT recipients have a two-fold increased risk of cancer-related mortality compared to the general population.¹ As the prevalence of SOT increases, factors such as long-term immunosuppression, underlying comorbidities, and graft survival contribute to the higher cancer burden in this population.^1-3 Non-melanoma skin cancers pose the greatest risk of cancer-related mortality in SOT recipients followed by non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and melanoma.¹ Immune checkpoint inhibitors (ICIs) are standard of care for many cancer types, including those that arise in SOT recipients. Unfortunately, prospective data evaluating ICIs in SOT recipients is limited due to their exclusion from clinical trials. This stems from the concern for ICI-induced graft rejection and diminished antitumor response in the setting of immunosuppressive medications.⁴ Despite the steady rise of annual SOTs performed over the past decade, there remains a lack of robust data on ICI outcomes and safety to guide clinical decision-making in this population. This review summarizes the current evidence for ICI therapy in SOT recipients.⁵

SOT recipients are at heightened risk for varying types of malignancies, partly due to long-term immunosuppressive therapy required to prevent graft rejection. Immunosuppression can increase the risk of several cancers by decreasing immunosurveillance. Oncogenic viruses can remain unchecked, leading to ineffective viral control, which is associated with higher rates of NHL, HL, anogenital cancers, and Kaposi sarcoma in patients post-transplant.³ SOT recipients are 65-250-times more likely than the general population to develop cutaneous squamous cell carcinoma (cSCC).⁶ The considerable increase in skin cancer risk is likely from chronic immunosuppression and the sensitizing effects of these medications to cause further DNA damage from ultraviolet radiation. Certain SOT subpopulations exhibit a greater risk for developing specific types of malignancies. For example, transplant recipients with chronic hepatitis B or C have an increased risk for developing hepatocellular carcinoma. Furthermore, some SOT recipients retain their native organ, like with kidney transplant, and are at risk of developing cancer in their native diseased organ. Primary sclerosing cholangitis and cystic fibrosis patients have an increased risk of colorectal cancer, and patients with these conditions that underwent a liver or lung transplant are inherently at a higher risk.³

ICIs are standard of care for many tumor types commonly seen in SOT. ICIs are monoclonal antibodies designed to block inhibitory pathways of the immune system, thereby enhancing activation and proliferation of T cells. With advancements in our understanding of the immune system, the mechanisms by which ICIs bolster immune activity have also evolved. Current ICI options include inhibitors of programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG-3) and cytotoxic T-cell lymphocyte associated protein 4 (CTLA-4). One major concern for using ICIs in transplant recipients is the increased risk for graft rejection.^2,7 While graft rejection is multifactorial, a major component is T-cell stimulation and activation which leads to cytotoxic effects on the donor organ.⁷ PD-L1 and PD-1 receptors can be expressed by the tumor, the graft, and graft-reactive T cells. Expression on the graft and graft-reactive T cells is associated with a greater risk of acute rejection.^2,8 Furthermore, PD-L1 is expressed on endothelial cells of the graft which has been attributed to developing vascular rejection in the setting of anti-PD-1/PD-L1 therapy.⁹ Graft rejection can occur rapidly, with studies reporting an observed median time to rejection of approximately 3 weeks, and most episodes of rejection occurring within 7 weeks.^2,10,11

Multiple studies have reported decreased graft rejection when immunosuppression is increased.^2,4,10,11 This poses a risk for diminishing ICI-induced antitumor activity. Data surrounding this concern is limited; therefore, evaluating efficacy of ICIs in SOT recipients can be challenging. However, emerging evidence suggests that despite concurrent immunosuppression, ICIs can produce meaningful antitumor responses in SOT patients, with variations based on cancer type, graft type, and ICI class.^2,4,10,11

Cancer Type

In SOT recipients, cutaneous malignancies, particularly cSCC, benefit more from ICIs when compared to non-cutaneous malignancies. Among 343 SOT recipients in a major systematic review, individuals with cSCC achieved a 57% one-year survival rate after ICI therapy. In contrast, patients with other cancers, primarily hepatocellular carcinoma (14.6%) and lung cancer (6.4%), had a lower one-year survival rate of 37%. Furthermore, the objective response rate (ORR) of 61% in individuals with cSCC aligns with similar response rates observed in the general population and was higher than the 26.9% response rate in SOT recipients with non-cutaneous malignancies. Patients with cSCC also had fewer incidences of acute rejection at 6-months (23.3%) compared to patients with other malignancies (45-57%).¹¹ The benefit of ICI therapy for cSCC was also reported in a phase 1 trial with 12 patients, which showed a 46% response rate, including two durable responses beyond one year.⁶

SOT recipients with melanoma or other non-cSCC solid tumor malignancies have worse survival outcomes than those with cSCC. Notably, a heightened risk of acute graft rejection has been seen in SOT recipients with melanoma.¹¹ The link between heightened acute graft rejection and melanoma is likely multifactorial and may be due to greater use of combination ICI therapy and molecular mimicry between melanoma neoantigens and graft antigens.^11,12 Murakami et al reported an OS benefit of ICI therapy in kidney transplant recipients (KTRs) with cSCC compared to those who did not receive ICIs (19.8 months vs 10.6 months, p = 0.016). However, the benefit of ICIs was not observed in KTRs with melanoma (13.5 months vs 11.4 months, p = 0.34).¹³

As demonstrated in previous studies, SOT recipients with cSCC are likely to benefit the most from ICI therapy compared to non-cutaneous solid tumors. However, positive outcomes with ICIs in non-cutaneous solid tumors have been reported in the INNOVATED trial.⁴ This was a multicenter, retrospective cohort trial that included 31 SOT patients with solid tumors, with 98% of the participants being KTRs. The most common non-cutaneous cancer types were lung (36%), genitourinary (13%), and gastrointestinal (6.5%). The response rate across the entire cohort was 45.2%. The SOT recipients with lung cancer showed a similar response rate of 45.5% and a median 6-month PFS of 32.7%, which aligns with data reported in phase III trials.⁴ Further research is needed to determine the true benefit of ICIs in non-cutaneous malignancies based on specific tumor type.

Graft Type

KTRs are the most studied population in which ICIs have been used. Saleem et al characterized outcomes of SOT recipients with advanced cancer receiving an ICI. In total, 343 patients were included. The most common transplanted organs were kidney (71%) and liver (22%). This systematic review found that when given ICI therapy, liver, lung, and heart transplant recipients had a greater mortality risk compared to KTRs (HR 1.95; 95% CI, 1.28-2.97). Interestingly, liver, lung, and heart transplant recipients experienced lower acute rejection rates (HR 0.58; 95% CI, 0.35-0.96) and lower risk of graft loss (HR 0.36; 95% CI, 0.14-0.96) after receiving an ICI.¹¹ Similar results are shown by another study that included 53 kidney transplants, 24 liver transplants, and 6 heart transplants. Median OS following an ICI was 36 weeks (95% CI, 25-56) in KTRs, 29 weeks (95% CI, 5-NR) in liver transplant patients, and 46 weeks (95% CI, 38-NR) in heart transplant patients. While this study showed greater OS in heart transplant recipients compared to Saleem et al, it is important to note that Saleem et al included three times as many heart transplant recipients. The study also showed higher rates of graft rejection in the KTRs (43%) compared to liver (38%) or heart (17%) transplant patients. The mean time from ICI initiation to rejection was 5.6 weeks, with 37.9% of patients showing signs of rejection within 2 weeks.¹⁴ These findings suggest that ICI therapy in KTRs is associated with more favorable survival, however outcomes are counterbalanced by higher rates of acute graft rejection and graft loss. It should also be noted that Saleem et al reported a higher percentage of cSCC patients than the second transplant study (32% vs 12%), which as previously described, confers with greater ICI response.

ICI Class

In an era where ICIs are standard of care for many malignancies, the decision to initiate an ICI is multifaceted and requires thoughtful consideration. ICIs remain a feasible option for transplant recipients facing life-threatening advanced malignancies when surgical intervention, radiation, or conventional chemotherapy are not appropriate. Additionally, reserving ICIs for salvage treatment and minimizing the use of combination ICI therapy may maintain the benefits of ICIs while delaying graft rejection. When ICIs are initiated, patients should undergo close monitoring within the first 2 months of treatment, as the risk of graft rejection is highest during this time.^2,11

Combination ICI therapy seems to be linked to a higher risk of graft loss, as demonstrated by one meta-analysis showing that 42.2% of patients experienced graft loss within one year of receiving combination ICIs, compared to 21% among those treated with PD-1/PD-L1 monotherapy.¹¹ However, when compared to Murakami et al, investigators showed that the ORR of combination therapy was 87.5% and was comparable to non-SOT patients receiving the same therapy. This study also showed an ORR of 9.1% for PD-1 inhibitors, which was lower in non-SOT patients receiving the same therapy (32-45%).¹³ Portuguese et al. reported that 6 out of 15 patients (40%) achieved an ORR with CTLA-4 monotherapy, compared to 30 out of 92 patients (32.6%) who received PD-1/PD-L1 monotherapy. Among the five patients treated with CTLA-4/PD-1 combination therapy, 60% (3/5) achieved an ORR. Additionally, the study found lower rejection rates with CTLA-4 monotherapy (26.7%) compared to PD-1 inhibitors (44.4%).² Furthermore, a separate systematic review analyzing a cohort of 57 patients found no statistically significant association between the type of ICI administered and graft rejection.¹⁵

Time from organ transplant to ICI initiation is another important consideration. One study reported a lower risk of graft rejection when ICIs were initiated more than 8 years post-organ transplant.^14,17 This may be due to the development of immunological tolerance and the use of fewer immunosuppressants as more time passes beyond transplant.^2,17 If an ICI is initiated, considerations must be made on the choice and amount of immunosuppression. While there are no guidelines to support specific immunosuppressants in the setting of ICI therapy, current evidence suggests that mammalian target of rapamycin inhibitors (mTORs) may preserve graft function and retain antitumor response.¹⁹

Discussion

Patients with a history of graft rejection are at an increased risk of experiencing ICI-induced graft rejection, potentially due to the reactivation of alloreactive T cells targeting the transplanted organ or the emergence of new cross-reactive T cells.^17,18 The benefits of initiating ICIs in this patient population must be heavily weighed against the consequences of graft rejection and graft failure. Non-kidney transplant recipients exhibit the poorest OS compared to other SOT recipients.^10,11 This disparity may be attributed to limited non-transplant treatment options for certain organ types. For instance, liver and heart transplant recipients lack access to organ-replacement therapies. Conversely, KTRs experiencing graft rejection or graft failure can transition to hemodialysis, which may allow for more extensive ICI use.

Identifying which SOT recipients may experience graft rejection following ICI initiation remains a significant research area. Most existing research has focused on non-invasive biomarker testing in KTRs. Current evidence shows that plasma donor-derived cell-free DNA (dd-cfDNA) levels are elevated prior to graft rejection after receiving ICI therapy. This rise in dd-cfDNA, before detectable rises in serum creatinine, has potential as a future biomarker to predict kidney transplant rejection.^18,19 Another biomarker of interest in KTRs is urinary chemokine C-X-C motif ligand 10 (CXCL-10). CXCL-10 is secreted by renal tubules and infiltrating immune cells and is a non-specific marker for inflammation.²⁰ One phase 1 trial reported increased urinary CXCL-10 in KTRs who developed graft rejection after an ICI.²¹ Non-invasive biomarker testing has also been evaluated in non-kidney transplant recipients. In a retrospective trial evaluating liver transplant recipients who received an ICI pretransplant, elevations in peripheral blood CD8+ T cells, interferon alpha, and tumor necrosis factor alpha were more pronounced in those who developed an immune-related adverse reaction (IRAE). A washout period of less than 30 days and the presence of IRAEs were identified as independent risk factors for graft rejection.²² There is no gold standard for predictive biomarkers for the development of graft rejection. More research is needed to assess predictive biomarkers of graft rejection as well as the relationship with IRAEs.

Conclusion

Managing advanced cancer and ICI use in SOT recipients is complex and necessitates multidisciplinary discussions involving oncology, transplant, and the patient. For all SOT recipients and their caregivers, education on the risks of developing cancer and adhering to cancer screening recommendations is crucial for early cancer detection and improving treatment outcomes. Cancer screenings for SOT recipients follow the general guideline recommendations as there are no SOT-specific cancer screening protocols to date.¹⁶ More research is needed to determine the optimal ICI regimen, timing of ICI initiation, and most appropriate immunosuppressive regimen to balance graft rejection and antitumor response. Non-invasive biomarkers' prediction of graft rejection remains an ongoing area of investigation.