Background
Transplantation of allogeneic solid organs is an established modality for the management of end-stage organ failure with >39,000 transplants performed annually in the United States and an overall prevalence exceeding 270,000 patients with functioning solid organ allografts.1–3 Cancer is a leading cause of morbidity and mortality in solid organ transplant recipients (SOTRs),4 with a >2-fold higher cancer incidence compared with the US general population.5 The burden of cancer in this special population is expected to increase in association with an increasing total number of transplants performed, longer graft survival, older recipient age, and a decline in the competing risk of cardiovascular mortality.6
A recent large US retrospective study of skin cancer in SOTRs documented that skin cancers are the most common cancer, affecting 8% of transplant recipients. Cutaneous squamous cell carcinoma (cSCC) was the dominant histology, representing 91% of skin cancer diagnoses, followed by melanoma (8%), and Merkel cell carcinoma (<1%). The incidence rate per 100,000 person-years for cSCC was 36 times higher than for the US general adult population.7
Much of the increased cancer risk associated with organ transplantation is a consequence of chronic immunosuppressive agents targeting T-cell alloimmunity required for graft survival (Figure 1). Chronic immunosuppression blunts recipient T-cell responses specific for viral and nonviral antigens, including mutation-associated antigens contributing to impaired immune surveillance against transformed cells.
Impact of immunosuppressive agents on the alloimmune T-cell response. The alloimmune response occurs when a naïve T cell receives 3 signals, signal 1: antigen presented by dendritic cells binds its cognate T-cell receptor and the signal is transduced via CD3; signal 2: CD80 and CD86 on the dendritic cell surface bind CD28 on the T cell; and signal 3: lymphocyte proliferation is driven by IL-2 and other cytokines generated from signal transduction pathways. The goal of immunosuppression is to induce partial T-cell anergy, or “adaptive tolerance,” primarily by interfering with signals 1 and 3. Induction medications include high-dose glucocorticoids and biologic antibodies (eg, anti–IL-2 antibody [basilixumab] and antithymocyte globulin). Maintenance therapy traditionally includes glucocorticoids and calcineurin inhibitors (eg, cyclosporine and tacrolimus). Calcineurin inhibitors act by disrupting signal 1. Other agents function by impairing signal 3–induced proliferation. These include mTOR inhibitors (eg, sirolimus and everolimus) and antimetabolites (eg, azathioprine, methotrexate, and mycophenolate).
Abbreviations: G1, gap 1; G2, gap 2; M, mitosis; MHC, major histocompatibility complex; S, DNA synthesis; TCR, T-cell receptor.
Citation: Journal of the National Comprehensive Cancer Network 20, 4; 10.6004/jnccn.2022.7009
Spontaneously arising antitumor immunity is also the substrate for manipulation by anticancer immunotherapies, including immune checkpoint blocking antibodies that disrupt coinhibitory signaling on activated T cells. Since FDA approval of the first immune checkpoint inhibitor (ICI), ipilimumab, in 2011, 8 ICIs have been approved that target CTLA-4 (ie, ipilimumab), PD-1 (ie, nivolumab, pembrolizumab, cemiplimab, dostarlimab), or PD-L1 (ie, atezolizumab, avelumab, durvalumab) for 19 different cancer types (see supplemental eTable 1, available with this article at JNCCN.org). A recent analysis estimates that nearly half of all US patients with advanced or metastatic cancers are now eligible for treatment with ICIs.8
Due to the need for chronic immunosuppressive therapy, SOTRs with cancer have been consistently excluded from clinical trials with ICIs.9–16 Thus, clinical outcomes for cancers arising in SOTRs treated with ICIs reflect a postmarketing experience with commercially available ICIs. Case reports and previous reviews have demonstrated that ICIs retain anticancer activity among SOTRs with cancer despite the concurrent use of chronic immunosuppression, but carry a significant risk of triggering allograft rejection and failure.17–19 In this review, we have compiled the largest number of published cases of advanced cancers arising in SOTRs treated with ICI that have been analyzed to date. We have quantified key clinical outcomes for cancer control and graft survival and examined their associations with coadministered immunosuppressive agents.
Methods
PubMed, Google Scholar, and Embase were queried for cases of ICI use in SOTRs from January 1, 2010, to November 1, 2021. Search strings are described in supplemental eTable 2. Cases were included for analysis if ICI was given following a SOT. Only published case reports or series were included. Non-English language articles and conference abstracts were excluded.
Cases were primarily identified utilizing a PubMed search (928 results). Additional cases were identified with 2 Google Scholar searches (359 results), and an Embase search (605 results). A.J. Portuguese performed a review of title and abstract to determine which references seemed potentially relevant, then screened the text of these results for inclusion. Of the potentially relevant results, 74 publications were identified for inclusion, encompassing 119 appropriate cases. Clinical features and outcomes are detailed in supplemental eTable 3.
Associations between patient- and treatment-related factors were assessed using logistic regression. For factors that contained >1 category, a global test was used to test the hypothesis that the proportions of the relevant outcome were the same across categories. Objective response rate (ORR) was defined as complete response (CR) or partial response (PR).
Results
Patients
Patient characteristics are shown in Table 1. The total cohort included 119 patients. Median patient age was 62.0 years (interquartile range [IQR], 54.0–68.3 years) and there were more men (n=82; 68.9%) than women (n=35; 29.4%). Allografted organs included kidney (n=64; 53.8%), liver (n=43; 36.1%), heart (n=7; 5.9%), cornea (n=2; 1.7%), lung (n=1; 0.8%), pancreas and kidney (n=1; 0.8%), and heart and kidney (n=1; 0.8%). Involved cancers included cutaneous melanoma (cMEL; n=42; 35.3%), hepatocellular carcinoma (HCC; n=27; 22.7%), cSCC (n=22; 18.5%), non–small cell lung cancer (n=7; 5.9%), Merkel cell carcinoma (n=3; 2.5%), colorectal cancer (n=3; 2.5%), renal cell carcinoma (n=3; 2.5%), ocular melanoma (n=3; 2.5%), and intrahepatic cholangiocarcinoma (n=1; 0.8%).
Patient Characteristics (N=119)
The distribution of cancer types differed by allograft. For example, skin cancers were the most frequently observed tumors in kidney transplant recipients (KTRs; cMEL: 29/64, 45.3%; and cSCC: 18/64, 28.1%) and heart transplant recipients (cMEL: 6/7, 85.7%). All cases of HCC occurred in liver transplant recipients (LTRs; 27/43, 62.8%), among whom skin cancers occurred less frequently (cMEL: 6/43, 14.0%; and cSCC: 3/43, 7.0%).
Median time from transplant to the start of ICI therapy was 6.6 years (IQR, 3.0–12.0 years). Ninety patients were treated with anti–PD-1 therapy alone (n=90; 75.6%). Treatments included nivolumab (n=40; 33.6%), pembrolizumab (n=33; 27.7%), cemiplimab (n=10; 8.4%), toripalimab (n=6; 5.0%), and camrelizumab (n=1; 0.8%). Fifteen patients were treated with anti–CTLA-4 alone with ipilimumab (n=15; 12.6%). Two patients were treated with anti–PD-L1 therapy with avelumab (n=1; 0.8%) or atezolizumab (n=1; 0.8%). Twelve patients were treated with concurrent (n=5; 4.2%) or sequential anti–CTLA-4 plus anti–PD-1 therapy (n=7; 5.9%).
Cancer Control Outcomes
The ORR for the entire cohort was 34.5% (n=41), and was 35.7% (15/42), 18.5% (5/27), and 68.2% (15/22) for cMEL, HCC, and cSCC, respectively. Anecdotal reports of response for colorectal cancer, urothelial cancer, and renal cell carcinoma were reported. Median duration of objective response (DoR) was 8.0 months (IQR, 5.5–15.0) for the entire cohort, and ranged from 6.0 to 9.0 months for the 3 most common tumor types (Table 2). ORR was also analyzed by the ICI target, which was 33.3% (30/90) for PD-1, 40.0% (6/15) for CTLA-4, and 60.0% (3/5) for combination PD-1/CTLA-4 (supplemental eTable 4).
Outcomes of ICI Treatment for the Overall Cohort and Most Common Cancer Types
Patient and treatment factors analyzed for their association with ORR are shown in Table 3 and Table 4, respectively. Compared with the other cancer types, cSCC demonstrated superior ORR (68.2 vs 26.8%; odds ratio [OR], 5.85; 95% CI, 2.15–15.96; P =.0006). Factors associated with improved ORR included greater time from transplant to ICI (OR, 1.09; CI, 1.02–1.16; P =.008, modeled as a continuous linear variable), preemptive reduction in intensity of the graft maintenance immunosuppressive regimen prior to the start of ICI treatment (50.0% vs 18.5%; OR, 4.40, 95% CI, 1.45–13.32; P =.0088). In a multivariable analysis, both cSCC (OR, 10.20; 95% CI, 2.87–36.29; P =.00034) and preemptive reduction in intensity of the graft maintenance immunosuppressive regimen (OR, 3.68; 95% CI, 1.16–11.63; P =.027) were associated with improved ORR (supplemental eTable 5). In all SOTRs combined, no individual immunosuppressive agent used for allograft maintenance, or the total number of agents used showed a definitive association with ORR.
Patient Factors Analyzed for Association With Objective Response
Treatment Factors Analyzed for Association With Objective Response
The number of patients for whom tumor PD-L1 status was known was limited, and therefore the association of PD-L1 positivity with outcome was difficult to interpret. Among those with data, 4 of 5 (80%) patients with positive tumor PD-L1 had an objective response compared with 0 of 3 whose tumors were negative.
ICI-Associated Toxicity
Among the entire cohort, graft rejection and graft failure occurred in 41.2% (n=49) and 23.5% (n=28), respectively. Allograft rejection occurred in 48.4% (31/64) of KTRs and only 30.2% (13/43) of LTRs, whereas allograft failure occurred in 25.0% (16/64) of KTRs and 20.9% (9/43) of LTRs. For cases in which the time to rejection was reported (33/49; 67.3%), the median time to rejection was 3.0 weeks (IQR, 1.7–5.0 weeks). Most cases occurred within the first month (21/33; 63.6%), and almost all occurred within the first 7 weeks (27/33; 81.8%) (Figure 2).
Time to allograft rejection from initiation of immune checkpoint inhibitor therapy. Frequency and cumulative percentage of cases of allograft rejection are shown. The noncumulative percentage of cases of rejection occurring in the specified time period are listed above the blue bars.
Citation: Journal of the National Comprehensive Cancer Network 20, 4; 10.6004/jnccn.2022.7009
Non–graft-related immune-related adverse events (irAEs) were reported in 13.4% (n=16) of the total cohort. The most common irAEs included pneumonitis (6/16; 37.5%), dermatitis (5/16; 31.3%), colitis (4/16; 25.0%), and hepatitis (2/16; 12.5%).
Patient and treatment factors analyzed for their association with graft rejection are shown in Table 5 and Table 6, respectively. In the current analysis, the rejection rate was numerically higher in patients with a history of prior rejection but the observed difference was not statistically significant (50.0% vs 36.7%; OR, 1.72; 95% CI, 0.51–5.84; P =.38). Similar to the outcome of ORR, the association of PD-L1 positivity of lymphocytes within the allograft with rejection was difficult to interpret due to the limited data. All 7 patients (1/1 KTR, 6/6 LTR) known to have PD-L1–positive lymphocytes within the allograft had post-ICI rejection, and none of the 8 patients (0/0 KTR, 8/8 LTR) known to be negative experienced graft rejection (P<.0001).
Patient Factors Analyzed for Association With Rejection
Treatment Factors Analyzed for Association With Rejection
We observed that the probability of rejection decreased as the number of immunosuppressive agents increased (OR, 0.60; 95% CI, 0.36–1.00; P =.05, number of agents modeled as a continuous linear variable). Among the individual immunosuppressive agents used, less rejection was seen with tacrolimus (25.6 vs 48.7%; OR, 0.36; 95% CI, 0.16–0.85; P =.019), whereas there was no evidence of reduced rejection for another calcineurin inhibitor, cyclosporine (50.0% vs 40.5%; OR, 1.47; 95% CI, 0.28–7.60; P =.65). In a multivariable analysis, use of tacrolimus was associated with less rejection (OR, 0.24; 95% CI, 0.093–0.60; P =.0023; supplemental eTable 6).
LTRs and KTRs were separately analyzed for an association between immunosuppressive agents and rejection. Among LTRs, less rejection was seen only with tacrolimus use (17.4% vs 47.4%; OR, 0.23; 95% CI, 0.06–0.95; P =.04); whereas among KTRs, less rejection was seen with both steroid (38.3% vs 75.0%; OR, 0.21; 95% CI, 0.58–0.74; P =.015) and everolimus use (16.7% vs 54.9%; OR, 0.16; 95% CI, 0.03–0.83; P =.028; supplemental eTable 7). In a multivariable analysis of KTRs, use of everolimus was associated with less rejection (OR, 0.11; 95% CI, 0.016–0.72; P =.021; supplemental eTable 8).
Cause of Death
Of the patients who died (n=50), the most common causes of death were progressive disease (32/50; 64.0%) and graft failure (12/50; 24.0%). Among KTRs who developed ICI-induced allograft rejection, progressive disease remained the most common cause of death (5/9; 55.6%), whereas graft failure was the most common cause of death among LTRs (8/11; 72.7%).
Discussion
For many SOTRs diagnosed with advanced cancer, the most effective anticancer treatment available will be an ICI. The 2 major concerns of ICI use among SOTRs include diminished anticancer efficacy and acute allograft rejection. Unfortunately, no prospective clinical trial data are available to help guide management. This systematic review represents the largest collection of SOTRs treated with ICIs to date.
Our analysis demonstrates that ICIs retain significant anticancer activity in the SOTR population. Objective responses occurred in approximately one-third of SOTRs, including CRs in 13.4% of patients, and many responses were durable and ongoing at the time of reporting. However, compared with tumors arising outside the context of SOT, the depth and duration of response may be compromised by the need for concomitant immunosuppression to maintain the allograft. For example, historic trial data for cMEL and HCC treated with nivolumab monotherapy demonstrated an ORR of 45% (median DoR, not reached at 5 years) and 20% (median DoR, 17 months), respectively. 20, 21 Among SOTRs with cMEL and HCC, we found inferior ORRs of 35.7% (median DoR, 6 months) and 18.5% (median DoR, 9 months), respectively. We also found that the ORR was compromised by treatment delivered close in time to transplant induction immunosuppressive treatments, an association noted previously.17 In addition, a preemptive reduction in the intensity of the immunosuppressive regimen also showed a positive association with ORR.
The most frequently occurring cancer among SOTRs is cSCC.22 Treatment of cSCC with ICIs was associated with a better ORR (68.2%) than the other cancers in our study, and compared favorably to benchmark ORRs (34.3%–41%) collected in non-SOTRs. Additionally, confirmed median DoR was similar (9 vs 6 months, respectively).23,24 Cases of cSCC occurred primarily among KTRs. The preferential association of cSCC with KTR and the basis for the superior response profile remain a matter of speculation. Given that the risk of posttransplant cSCC has been shown to be related to the intensity of chronic immunosuppression in SOTRs,25 KTRs are at higher risk than LTRs, and treatment with ICIs may reverse some aspect of impaired immunosurveillance in this setting.
Allograft rejection was the most frequent immune-related toxicity developing in SOTRs in comparison with other irAEs. Rejection occurred rapidly after initial exposure to ICIs. We observed a median time to rejection of 3 weeks, a finding concordant with a prior study.26 Nearly all episodes of rejection occurred within 7 weeks. A history of prior allograft rejection was previously reported as a risk factor for post-ICI rejection17; however, we did not observe this finding in our analysis. These data encourage the frequent monitoring of SOTRs at the time of initiating ICI treatment, with the goal of early detection of organ rejection to enable rapid initiation of antirejection therapy when indicated.
Allograft rejection occurred more commonly among KTRs than LTRs, yet allograft failure occurred at a similar rate. For KTRs who developed rejection, progressive disease remained the most common cause of death. However, among LTRs with rejection, graft failure was the dominant cause of death in this subgroup. The finding of higher morbidity associated with rejection of nonkidney transplants is not surprising, because many KTRs who experience rejection can be managed with dialysis, whereas LTRs and other SOTRs do not have a comparable supportive option.
Preemptive modification of the immunosuppressive regimen used in combination with ICI to optimize allograft maintenance without compromising tumor response has been the focus of prior analyses. For example, anecdotal successes have been achieved using an induction steroid taper.27–30 In our analysis, tacrolimus showed an association with reduction in post-ICI rejection without dampening of cancer response. Among the LTR subset, the beneficial effect of tacrolimus was redemonstrated. However, this effect was not seen among KTRs, who appeared to derive benefit from everolimus, and possibly steroids. The benefit of mTOR inhibitors in the KTR population was also previously observed by Murakami et al.19 Other investigators have associated sirolimus with more favorable outcomes for anti–PD-1 toxicity and efficacy in the SOTR population.30–32 However, sirolimus did not have a significant impact on ORR or rejection in our analysis.
Tumor PD-L1 expression is a validated predictive biomarker to select for ICI use in many tumor types; however, not for the most common tumors present in our analysis, including cMEL, HCC, and cSCC. Several small studies have evaluated allograft PD-L1 status as a potential new tool for prediction of rejection risk.33–38 Positivity, defined as ≥1% of allograft lymphocytes with membrane PD-L1 staining, showed a provocative association with graft rejection in the small number of cases evaluated. All graft PD-L1 positives (7/7) and all negatives (8/8) experienced rejection and no rejection, respectively, a finding consistent with murine models.39,40 If the role of graft PD-L1 expression is confirmed in larger series, patients with positive allograft PD-L1 staining may be candidates for closer monitoring for rejection, for more intensive immunosuppressive maintenance, and/or for ICI regimens deemed to have less potential for induction of rejection. The impact of such approaches on antitumor efficacy will need to be evaluated.
This study has several limitations. First, because our data were ascertained from published reports, reporting bias may favor the dissemination of particularly good or bad outcomes. Second, despite the greater number of cases than in prior systematic reviews, the sensitivity of comparison testing remains limited by sample size. Third, the published reports contained neither complete data nor longitudinal follow-up for each case. Ongoing response was documented in many reports at the time of publication, limiting our ability to determine true DoR.
Management of SOTRs with advanced cancer is challenging, particularly in the era of ICIs. Prospective clinical trials are needed to help determine the optimal strategy for immunosuppressive management and surveillance for graft rejection. To this end, a prospective phase I trial (ClinicalTrials.gov identifier: NCT03816332) is currently ongoing to assess the use of tacrolimus in conjunction with ICIs among KTRs with advanced skin cancers. Our center has launched the first-of-its kind Cancer and Organ Transplant Clinic at Fred Hutchinson Cancer Center and University of Washington Center for Innovations in Cancer & Transplant, bringing together medical oncology and transplant specialists to facilitate the co-management of the SOTR initiating cancer immunotherapy treatment.
Conclusions
Our analysis provides current benchmark data to help guide clinicians’ approach to the management of SOTRs with advanced cancers that are reflected by our patient cohort. Biomarker development, more robust datasets, and prospective study of concomitant immunosuppressive management may help refine decision making in this complex scenario in the future. Close coordination of care between the medical oncologist and transplant specialist is encouraged to help optimize treatment outcomes.
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