The widespread use of immunotherapy in the management of cancers has led to improved overall survival and progression free survival. Due to increased risk of allograft rejection, organ transplant recipients are often excluded in clinical trials or offered immunotherapy only as salvage therapy. We report a case of successful use of Cemiplimab, an immune checkpoint inhibitor, in a high immunologic risk kidney transplant recipient who was diagnosed with metastatic squamous cell carcinoma (SCC) twenty-five months post-transplant. He started Cemiplimab five months post diagnosis of SCC, as third line therapy, after demonstrating progression of metastatic skull-based disease on prior lines of therapy. His maintenance immunosuppression was changed from triple immunosuppression with tacrolimus, mycophenolate and prednisone to sirolimus with a high trough target of 10-15 ng/mL and steroid therapy. He tolerated the high sirolimus trough and continued on Cemiplimab for six months with clinically stable allograft function and a good quality of life. Notably, he demonstrated response of his previously chemotherapy refractory metastatic disease. He passed away from radiation necrosis of the brain at sixty-eight months post-transplant.

Posttransplant lymphoproliferative disorders (PTLDs) are a well-known complication of solid organ transplantation and allogeneic hematopoietic stem cell transplantation. The diffuse large B-cell lymphoma subtype (PT-DLBCL) is the most frequent monomorphic PTLD and is associated with poor prognosis. Transplant recipients have an increased risk of abnormal proliferation of lymphoid cells because of diminished immune surveillance. In about 60% of the cases, Epstein-Barr virus infection seems to contribute to the cancer phenotype. Although clinical and research interest in the disorder has increased during the last two decades, the pathology of the disease remains largely elusive. In this review, we summarize current knowledge of PT-DLBCL pathogenesis, and we discuss how a better understanding of PT-DLBCL can lead to improved diagnostics and therapeutic strategies.

Over the last decade, immune checkpoint inhibitors (ICIs) have been established as an integral component of the contemporary anticancer armamentarium. In dermatology, ICIs are most established as treatment of advanced melanoma. However, emerging evidence has demonstrated that their utility in cutaneous oncology extends to a variety of other non-melanoma malignancies. This review provides an update of the evidence from clinical trials, real world analyses, and translational research over the last three years in cutaneous malignancies beyond melanoma. Special focus is presented on areas warranting further evaluation - including populations underrepresented in or excluded from clinical trials; new and emerging treatment scenarios beyond patients with metastatic disease; novel combination approaches; and the urgent need for reliable predictive biomarkers to identify predictors of response. Collaboration between oncologists, dermatologists and dermatological surgeons is essential to progress our understanding and treatment of patients with advanced cutaneous malignancies.

Studies on the safety of immune checkpoint inhibitors (ICIs) prior to liver transplantation (LT) are still limited to case reports or case series. It is vital to be aware of possible risk of transplant rejection with regards to ICIs after LT.

To explore the possible risk of transplant rejection induced by ICIs in hepatocellular carcinoma (HCC) patients and investigate the safe washout interval between ICIs administration and LT.

HCC patients from 3 tertiary hospitals in China who received ICIs prior to LT over the past 5 years were analyzed retrospectively. Patients who had experienced transplant rejection were reported in detail. Additionally, a comprehensive search of databases was conducted to identify case reports of HCC patients who underwent LT after receiving ICIs until October 1, 2024.

In our study, a total of 25 patients were analyzed. Programmed cell death protein 1 (PD-1) inhibitors were most commonly used (68 %, 17/25). The median interval between the last dose of ICIs and LT was 64 (40-150.75) days. Three patients (12 %) experienced T-cell mediated rejection (TCMR), 1 of which was induced by ICIs, and the other 2 of which could not be excluded from the influence of immunosuppressant concentrations. In literature review, a total of 96 cases of HCC patients who had received ICIs prior to LT were included. PD-1 inhibitor monotherapy resulted in significantly higher rejection than PD-L1 inhibitor monotherapy and other ICIs combination regimens (P = 0.021). In patients with pembrolizumab, the interval from ICIs to LT was shorter in the rejection group than in the non-rejection group (P = 0.045). Twenty-one cases (21.88 %) experienced transplant rejection, and 3 patients passed away following transplant rejection.

ICIs prior to LT was associated with the risk of transplant rejection, especially with factors such as the type of ICIs and the interval between ICIs and LT. Multicenter prospective studies are needed to further explore the safety of ICIs.

Solid organ transplant recipients (SOTRs) exhibit an elevated incidence and aggressiveness of squamous cell carcinomas (SCCs) due to their immunosuppression. These tumors are associated with a heightened risk of metastasis and increased mortality. Therefore, an appropriate management of these patients is essential to improve their prognosis. Given the scarcity of studies on non-melanoma skin cancers (NMSCs) in SOTRs, this article aims to summarize and analyze the evidence gathered to date regarding therapeutic approaches, personalized monitoring, and prevention strategies for SCCs in these patients. Additionally, recent advancements in understanding SCCs within this patient group are also documented.

Solid organ transplant recipients (SOTRs) are particularly prone to developing malignancies, often manifesting multiple tumors and tumors with a heightened susceptibility to metastasis, resulting in much lower survival rates when compared to the general population. Among these, cutaneous squamous cell carcinoma (CSCC) respresent a major challenge in terms of morbidity and mortality following organ transplantation. The management of post-transplant CSCC requires expertise from various disciplines, including dermatology, maxillofacial surgery, transplant medicine, radiation oncology, and medical oncology. Furthermore, the unique behaviors and prevalence of tumors in SOTRs necessitate tailored pathways for screening and treatment, distinct from those designed for immunocompetent patients. Despite the proven efficacy of immune checkpoint inhibitors (ICIs) in several cancers, SOTRs have often been systematically excluded from clinical trials due to concerns about potential allograft rejection and loss. Consequently, most data on the safety and efficacy of ICIs in SOTRs are derived from case series and reports. Given the significant risks involved, alternative therapeutic options should be thoroughly discussed with patients before considering ICI therapy. This literature review aims to provide an overview of CSCC in SOTRs, with a specific emphasis on therapeutic and screening strategies, particularly highlighting immunotherapy.

Cancer is a major cause of morbidity and mortality in kidney transplant patients. Unfortunately, the use of new anti-cancer therapies such as immune checkpoint inhibitors (ICPIs) in this population has been associated with rejection rates up to 40%, in retrospective studies. The main challenge is to maintain the patient in a delicate immunologic balance in which, while antitumor therapy defeats cancer the graft is safely protected from rejection. Recent clinical trials with ICPI have included kidney transplant recipients (KTRs) and the results advocate for a paradigm shift in the management of basal immunosuppression. This suggests that downward adjustments should be avoided or, even better, that this adjustment should be "dynamic." This review summarizes the latest scientific evidence available in renal transplantation under ICPI treatment: case series, prospective studies, histopathologic diagnosis, immunosuppression regimens and new biomarkers. This article will provide the latest information in on this specific field, allowing nephrologists to gain valuable knowledge and to be aware of new approaches to immunosuppression management in oncological kidney transplant patients.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, with 15% of cases arising on a background of non-alcoholic fatty liver disease (NAFLD). NAFLD is a heterogenous condition ranging from fatty liver to cirrhosis and is itself a growing global problem, with estimated worldwide prevalence of 50% in 2040. Pathophysiology of NAFLD-HCC is not well understood, there are no dedicated screening programs, and there have been no clinical studies of anti-cancer treatments in this population specifically. However, the NAFLD-HCC population appears different than other aetiologies - patients tend to be older, diagnosed at more advanced stages, have more comorbidities, and overall worse prognosis. Understanding of best treatment options for this group of patients is an urgent unmet clinical need. This narrative review discusses NAFLD-HCC pathophysiology and systemic treatment, and offers suggestions for future directions in this therapy area.

Kidney transplant (KT) recipients have an increased risk of malignancy due to chronic immunosuppression. The emerging use of immune checkpoint inhibitors (ICIs) has been a promising development for the treatment of malignancy, but their use adds to the complexity of immunosuppression management for KT recipients. This case report describes 2 cases of acute rejection in KT recipients following ICI initiation and discusses the balance of malignancy treatment with adequate immunosuppression.

The first patient is a 44-year-old male KT recipient with a diagnosis of metastatic renal cell carcinoma presenting with acute kidney injury 6 days following initiation of an ICI. The second patient is a 73-year-old male KT recipient with a diagnosis of squamous cell carcinoma presenting with acute kidney injury 2 weeks following initiation of an ICI.

Both patients were diagnosed with acute rejection in the setting of reduced immunosuppression and initiation of an ICI.

Both cases received an increased dose of steroid without improvement of graft function. The first patient subsequently underwent a delayed graft nephrectomy due to complications of acute rejection, whereas the second patient did not undergo nephrectomy.

The first patient experienced complications including perioperative bleeding requiring multiple operations, but ultimately stabilized on hemodialysis and showed a durable response to ICI. The second patient remained dialysis-dependent post-ICI treatment and was readmitted with allograft complications leading to his eventual death.

This study underscores the complexity of managing KT recipients diagnosed with malignancy and receiving ICIs. The balance between immunosuppression reduction to treat malignancy and preventing allograft rejection presents a significant challenge. Key considerations include the risk of acute allograft rejection and patient-centered decision-making. These cases highlight the need for further research to develop evidence-based guidelines for managing this patient population. In addition, the patient perspective in this study highlights the importance of careful risk-benefit analysis and the impact of treatment decisions on patient-focused outcomes.

Immune checkpoint inhibitor (ICI) therapy has enabled a paradigm shift in Oncology, with the treatment of metastatic cancer in certain tumor types becoming akin to the treatment of chronic disease. Kidney transplant recipients (KTR) are at increased risk of developing cancer compared to the general population. Historically, KTR were excluded from ICI clinical trials due to concern for allograft rejection and decreased anti-tumor efficacy. While early post-marketing data revealed an allograft rejection risk of 40%-50%, 2 recent small prospective trials have demonstrated lower rates of rejection of 0%-12%, suggesting that maintenance immunosuppression modification prior to ICI start modulates rejection risk. Moreover, objective response rates induced by ICI for the treatment of advanced or metastatic skin cancer, the most common malignancy in KTR, have been comparable to those achieved by immune intact patients. Non-invasive biomarkers may have a role in risk-stratifying patients before starting ICI, and monitoring for rejection, though allograft biopsy is required to confirm diagnosis. This clinically focused review summarizes current knowledge on complications of ICI use in KTR, including their mechanism, risk mitigation strategies, non-invasive biomarker use, approaches to treatment of rejection, and suggestions for future directions in research.

Graft-versus-host disease (GvHD) is a rare but severe complication following liver transplantation (LT), occurring in 1-2 % of cases with a mortality rate exceeding 80 %. Immune checkpoint inhibitors (ICIs) used pretransplant are associated with increased allograft rejection risk, but their impact on GvHD in LT remains unclear. Dominant one-way donor-recipient human leukocyte antigen (HLA) matching is a known risk factor for GvHD. This report presents a rare case of fatal GvHD in a hepatocellular carcinoma (HCC) patient treated with PD-1 inhibitors before LT and transplanted with a liver graft from a deceased donor with donor-dominant one-way HLA matching.

A 59-year-old male with a 30-year history of hepatitis B and unresectable HCC underwent LT after receiving the last dose of PD-1 inhibitors 7 days prior to the transplant. On post-operative day (POD) 12, the patient developed a skin rash, fever, and vomiting, and was diagnosed with GvHD. Despite aggressive treatment, including high-dose corticosteroids and extracorporeal membrane oxygenation (ECMO), the patient succumbed to gastrointestinal bleeding and multi-organ failure on POD 30. HLA genotyping revealed typical donor-dominant one-way HLA matching.

This case highlights a potential link between pretransplant exposure to ICIs and GvHD, particularly with donor-dominant one-way HLA matching. Residual anti-PD-1 antibodies may activate graft-resident immune cells, precipitating GvHD. Further research with larger cohorts and animal models is required to clarify this relationship and understand the underlying mechanisms.

Besides allograft rejection, caution should also be exercised regarding GvHD in patients with prior exposure to ICIs before LT.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, including the two most common liver tumors, hepatocellular carcinoma and cholangiocarcinoma, but their use in the peri-transplantation period is controversial. ICI therapy aims to heighten cytotoxic T lymphocytes response against tumors. However, tumor recurrence is common owing to tumor immune response escape involving ablation of CTL response by interfering with antigen presentation, triggering CLT apoptosis and inducing epigenetic changes that promote ICI therapy resistance. ICI can also affect tissue resident memory T cell population, impact tolerance in the post-transplant period, and induce acute inflammation risking graft survival post-transplant. Their interaction with immunosuppression may be key in reducing tumor burden and may thus, require multimodal therapy to treat these tumors. This review summarizes ICI use in the liver transplantation period, their impact on tolerance and resistance, and new potential therapies for combination or sequential treatments for liver tumors.

The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.

Chemoimmunotherapy is currently the preferred first-line treatment option for the majority of patients with advanced non-small cell lung cancer without driver genetic alterations. Most of these patients, however, will experience disease progression within the first year after treatment initiation and both patients and their physicians will be confronted with the dilemma of the optimal second-line treatment. Identification of molecular targets, such as KRASG12C, BRAFV600X, METexon14, and human epidermal growth factor receptor 2 mutations, and RET rearrangements offer therapeutic opportunities in pretreated patients with corresponding alterations. For those tumors that do not harbor oncogenic drivers, second-line treatment with docetaxel remains the current standard of care despite modest efficacy. Strategies to challenge docetaxel include the combination of immune checkpoint inhibitors (ICIs) with tyrosine inhibitors of multiple kinases or with DNA damage response inhibitors, antibody-drug conjugates, and locoregional treatments for oligoprogressive disease. Next-generation immunotherapy strategies, such as T-cell engagers, immune-mobilizing monoclonal T-cell receptors, chimeric antigen receptor cell therapy, tumor infiltrating lymphocytes, and T-cell receptor cell therapy are being currently investigated in the quest to reverse resistance to ICIs. Importantly, the advent of these new agents heralds a novel spectrum of toxicities that require both the physician's and the patient's education. Herein, we review current and future strategies aiming to outperform docetaxel after chemoimmunotherapy failure, and we provide practical information on how to best communicate to our patients the unique toxicity aspects associated with immunotherapy.

Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have a 2- to 4-fold higher risk of developing cancer compared to the general population and post-transplant malignancy is the third most common cause of death in KTR. Moreover, it is well known that certain cancer types are overrepresented after transplantation, especially non-melanoma skin cancer. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, with remarkable survival benefit in a subgroup of patients. ICI are monoclonal antibodies that block the binding of specific co-inhibitory signaling molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand programmed cell death ligand 1 (PD-L1) are the main targets of ICI. Solid organ transplant recipients (SOTR) have been excluded from clinical trials owing to concerns about tumor response, allo-immunity, and risk of transplant rejection. Indeed, graft rejection has been estimated as high as 48% and represents an emerging problem. The underlying mechanisms of organ rejection in the context of treatment with ICI are poorly understood. The search for restricted antitumoral responses without graft rejection is of paramount importance. This review summarizes the current knowledge of the use of ICI in KTR, the potential mechanisms involved in kidney graft rejection during ICI treatment, potential biomarkers of rejection, and how to deal with rejection in clinical practice.

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in white-skinned populations. There is little information on the epidemiology of cSCC, and even less on advanced cases (acSCC). Therefore, we analyzed acSCC patients to describe their characteristics, management, and outcomes over time.

A single-center retrospective study was conducted over a period of 5 years, including all patients who started systemic therapy for acSCC. The patient characteristics, cSCC management, response to therapy, and survival were recorded. Patients were stratified into equal chronological periods (periods 1 and 2). A subgroup analysis was performed to compare patients who received immunotherapy (group 1) with those who did not (group 2).

The study included 127 patients, and patient numbers increased by an average of 19.7% per year. Most patients were male (88/127), elderly (mean 81.6 years), with comorbidities, and 27.6% were immunocompromised. The median overall survival (OS) was higher in period 2 (20 months) than in period 1 (10 months) (hazard ratio [95% confidence interval] = 0.62 [0.39; 0.98], p = 0.04). The risk of progression increased with age and immunosuppression. Of the 64 patients who received second-line therapy, 38 had immunotherapy (group 1) and 26 received other therapies (group 2). Immunotherapy reduced mortality and progression by 71% (p = 0.004) and 67% (p = 0.002), respectively.

Patients with acSCC are usually very frail and elderly. OS increased over time, with a twofold improvement between periods 1 and 2, whereas progression-free survival (PFS) did not increase. Access to immunotherapy reduced mortality in a majority of patients in period 2. Immunosuppression and advanced age were associated with lower PFS.

This review outlines the most up-to-date metastatic melanoma treatment recommendations and relevant risks for patients with solid organ transplants, patients with renal dysfunction, and patients with preexisting autoimmune conditions. These specific treatment populations were excluded from the original clinical trials, which studied immune checkpoint inhibitors and BRAF/MEK inhibitors in the advanced melanoma setting. We have synthesized the current body of literature, mainly case series and retrospective analyses, to reflect the evidence for the treatment of these special patient populations at present.

Immune-related adverse events (irAEs) are toxicities that arise after the administration of monoclonal antibodies targeting immune checkpoints (immune checkpoint inhibitors [ICIs]) in patients with cancer. They can occur at any time after initiation of ICI treatment, with a broad clinical phenotype that can be organ-specific or systemic. Although most irAEs manifest as mild to moderate signs and symptoms, severe forms of irAEs can lead to irreversible organ failure and have acute life-threatening presentations. Treatment should be tailored to the specific organ involved and the severity. Glucocorticoids are the first-line treatment for most irAEs, with immunosuppressants and biologics mainly used as second-line treatments.

Kidney transplantation is the ideal treatment modality for patients with end-stage kidney disease, with excellent outcomes post-transplant compared with dialysis. However, kidney transplant recipients are at increased risk of infections and cancer because of the need for immunosuppression. Kidney transplant recipients have approximately two to three times greater risk of developing cancer than the general population, and cancer is a major contributor to morbidity and mortality. Most of the increased risk is driven by viral-mediated cancers such as post-transplant lymphoproliferative disorder, anogenital cancers, and Kaposi sarcoma. Nonmelanoma skin cancer is the most frequent type of cancer in kidney transplant recipients, likely due to an interaction between ultraviolet radiation exposure and decreased immune surveillance. Occurrence of the more common types of solid organ cancers seen in the general population, such as breast, prostate, lung, and colorectal cancers, is not, or is only mildly, increased post-transplant. Clinical care and future research should focus on prevention and on improving outcomes for important immunosuppression-related malignancies, and treatment options for other cancers occurring in the transplant setting.

Kidney transplant recipients are at increased risk of malignancy as a result of immunosuppression and are increasingly exposed to checkpoint inhibitors (CPIs). However, CPI therapy can precipitate allograft rejection. This review aims to summarize the current literature describing the epidemiology, immunological mechanisms, diagnosis, and treatment of CPI-associated allograft rejection.Initial studies of CPIs suggested allograft rejection post commencement of CPIs occured commonly (40-60%), occurring between 2 and 6 weeks after CPI initiation, with a cancer response rate approaching 50%. More recent studies with predefined, structured immunosuppressive regimens have seen rejection rates of 0-12.5%, with rejection occurring later. Allograft biopsy remains the mainstay of diagnosis; however, noninvasive tools are emerging, including donor-derived cell-free DNA, urinary chemokine assessment, and defining alloreactive T-cell clones prior to or during CPI therapy.

Immune-oncology-based regimens have shown efficacy in advanced HCC and have been implemented as standard of care as first-line therapy. Their efficacy, including high response rates, and safety justify their evaluation in earlier disease stages. Following negative results for adjuvant sorafenib in the global STORM trial in 2015, 4 global phase 3 trials, featuring different immune checkpoint inhibitor combinations, entered in parallel the race in the adjuvant setting. The IMbrave050 trial, comparing adjuvant atezolizumab in combination with bevacizumab to active surveillance following curative-intent resection or ablation, was the first to report, fast-tracking the results of the first interim analysis and demonstrating an improvement in recurrence-free survival. The trial has provoked a discussion on the horizon of expectations from adjuvant treatment and the clinical relevance of efficacy endpoints. Moreover, major pathological responses reported from early phase 2 data in the neoadjuvant setting provide a strong rationale for the evaluation of these concepts in phase 3 trials. In this review, we summarize current evidence and outline future directions for systemic therapies in early-stage HCC.

With advances in tissue typing, organ preservation techniques, and clinical surgery, organ transplantation has gained popularity as a treatment option for various end-stage diseases. Allogeneic transplantation has been widely adopted and extensively researched in clinical practice. Despite significant breakthroughs and progress in immunosuppression, this procedure is still associated with several adverse reactions and complications. Therefore, there is a continuing need to explore new immunological approaches to provide fresh insights and guidance for clinical transplantation. CD8+ T cells, traditionally known for their cytotoxic function and their ability to recognize transplanted organs as "non-self" entities, display cytotoxicity. However, recent studies have unveiled that CD8+ T cells have various subtypes and functions that extend beyond conventional cytotoxicity. These CD8+ T cell subtypes include Effector CD8+ T cells, Memory CD8+ T cells, and CD8Treg cells. This review examines the immune regulatory mechanisms of CD8+ T cells in allogeneic transplantation and discusses the potential applications of CD8+ T cells in treating tumors in transplant recipients who are receiving immunosuppressive therapy. These findings offer theoretical guidance for reducing post-transplant rejection reactions and improving adverse prognoses, offering new hope for improved clinical survival rate.

The usage of immunotherapy to treat skin malignancies in transplant patients requires weighing the risk of acute organ transplant rejection with the potential reduction of antitumor efficacy by transplant immunosuppression. Reducing the duration of immune checkpoint inhibitor treatment may help prevent acute transplant rejection and late immune-related adverse events.

An allogenic kidney transplant patient who developed regionally metastatic cutaneous squamous cell carcinoma received four cycles of pembrolizumab with complete response to therapy. Therapy was discontinued due to fatigue, significant cancer response, and to reduce the risk of acute graft rejection. His renal function remained stable, and he achieved subsequent durable response after treatment discontinuation.

Organ transplant recipients with complete response to immunotherapy for cutaneous squamous cell carcinoma may continue to respond despite early treatment cessation. This may reduce the risks of late immune-related adverse events and acute graft rejection.

Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of immune suppression. Programmed death protein 1 (PD-1), a regulator of host immune activation, binds to programmed death-ligand 1 (PD-L1) to suppress the T-cell immune response. PD-1/PD-L1 pathway may play a role in PTLD. The objective was to describe intratumoral expression of PD-L1 and PD-1 in pediatric monomorphic PTLD, and assess if density of these cells is associated with progression-free survival (PFS) and overall survival (OS).

Clinical variables and outcome data were collected on B-cell monomorphic PTLD treated in Toronto, Canada between 2000 and 2017. Diagnostic area from tumor tissue was identified to count CD3-positive or PD-1-positive cells and CD3-negative lymphoma B cells or PD-L1-positive cells. CD3+ , PD-1+ , and PD-L1+ cell densities were compared between cases of PTLD. OS and PFS were analyzed.

We identified 25 cases of B-cell monomorphic PTLD; majority Burkitt lymphoma (32%) and diffuse large B-cell lymphoma (56%). All cases had CD3+ cells infiltrating the tumor, and median percentage of CD3+ cells was 14% (interquartile range: 6.2%-25%). Twelve cases (48%) had PD-1+ cell infiltrating (range: 1%-83%) and 13 cases (52%) had no PD-1+ cells infiltrating. Sixteen cases (64%) had PD-L1+ cells present; however, there was no PD-L1 expression on any Burkitt lymphoma tissue. When comparing PD-1 and PD-L1 expression, there was no difference in OS or PFS.

Intratumoral presence of PD-1+ and PD-L1+ cells varied in pediatric patients with monomorphic PTLD; however, no relationship to OS and PFS was identified.

Immune checkpoint inhibitors (ICI) are standard of care therapy for patients with cutaneous malignancies, the most frequently diagnosed cancers in solid organ transplant (SOT) recipients. The activity and rate of allograft rejection in SOT recipients with advanced skin cancers treated with ICI is understudied.

We conducted a retrospective analysis of SOT recipients with advanced melanoma, cutaneous squamous cell carcinoma (cSCC), and merkel cell carcinoma (MCC) who were treated with ICI. Unpublished cases from our institution and published cases from the literature were aggregated. Demographics, type of immunosuppressive therapy, type of ICI(s) administered, prior systemic therapies, tumor response to ICI, and evidence of organ rejection and/or failure were recorded. Objective response rates (ORR) and rates of graft rejection and failure are reported.

Ninety patients were identified; four patients from our institution and 86 unique patients from a literature review. ORR to first-line ICI for the entire cohort was 41.1% (37/90). ORR by tumor type was 31% (18/58), 64.3% (18/28), and 25.0% (1/4) for melanoma, cSCC, and MCC, respectively. The rate of graft rejection was 37.8% (34/90) with 61.8% (21/34) of these cases progressing to graft failure. Number of immunosuppressive agents (0, 1, 2, or 3) was inversely associated with rate of graft failure.

In this retrospective analysis, ICIs demonstrate clinical activity in SOT recipients with cutaneous malignancies; however, the rate of graft rejection is high. Treatment plans should be individualized through thorough interdisciplinary discussion. Immunosuppressive modifications may be considered prior to starting treatment, but when feasible, enrollment on clinical trials is preferred.

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in the world. Among many identified risk factors, immunosuppression is a major factor that contributes to cSCC development. Organ transplant recipients (OTRs) are at markedly increased risk of developing multiple cSCCs with a propensity for advanced metastatic disease, leading to significant morbidity and mortality. The severity of the cSCC phenotype in OTRs highlights the urgent need to identify effective preventive modalities in this population. Despite recent advances in skin cancer prevention (e.g., nicotinamide) and treatment (e.g., immune checkpoint blockade), these modalities have limited utility in OTRs due to the lack of efficacy or significant side effect. Topical treatments against precancerous skin lesions, actinic keratosis (AK), remain the primary strategy to prevent cSCC in OTRs, which also have significant deficiencies in this population. Herein, we review the epidemiology, risk factors, and current cSCC prevention strategies. We highlight the gaps and future clinical strategies to address cSCC risk in high-risk populations.

Posttransplant lymphoproliferative disorder (PTLD) is an important and potentially life-threatening complication of solid organ transplant and hematopoietic stem cell transplant (HSCT). Given the heterogeneity of PTLD and the risk of infectious complications in patients with immunosuppression, the treatment of this disease remains challenging. Monomorphic PTLD and lymphoma of B-cell origin account for the majority of cases. Treatment strategies for PTLD consist of response-adapted, risk-stratified methods using immunosuppression reduction, immunotherapy, and/or chemotherapy. With this approach, ∼25% of the patients do not need chemotherapy. Outcomes for patients with high risk or those who do not respond to frontline therapies remain dismal, and novel treatments are needed in this setting. PTLD is associated with Epstein-Barr virus (EBV) infection in 60% to 80% of cases, making EBV-directed therapy an attractive treatment modality. Recently, the introduction of adoptive immunotherapies has become a promising option for refractory cases; hopefully, these treatment strategies can be used as earlier lines of therapy in the future.

The systemic treatment of advanced cutaneous squamous cell carcinoma (cSCC) has seen significant developments in recent years. The anti-PD1 inhibitor cemiplimab has demonstrated efficacy in clinical trials, but real-world data are still limited. Here, we aimed to evaluate the efficacy and the safety of cemiplimab in a real-world clinical setting.

A retrospective analysis was carried out for all patients who received at least two doses of cemiplimab at our department between February 2020 and January 2023. Progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR) and adverse events (AEs) were evaluated.

Twenty-five patients were included with a median age of 78 (65-82) years. The median treatment duration was 48 (16-72) weeks. Five (20%) patients were immunocompromised. Sixteen patients (64%) developed AEs, including 36% serious AEs (SAEs) of grade ≥ 3. Six patients (24%) were withdrawn from treatment due to the occurrence of AEs. Among the 25 patients, 52% showed an objective response (3 complete and 10 partial responses), 76% had controlled disease and 24% experienced progression. Among the five immunocompromised patients, the ORR was 60%, while the DCR was 80%.

This retrospective real-world study revealed that locally advanced or metastatic cSCC could be effectively treated with cemiplimab even in elderly, polymorbid and immunocompromised patients.

Five percent of patients with cutaneous squamous cell carcinoma develop locally advanced or metastatic disease that is not amenable to definitive surgical or radiation therapy. Cemiplimab, an antibody against programmed death receptor-1, was approved in the United States for the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma in 2018. We performed a literature review on the use of cemiplimab in cutaneous squamous cell carcinoma, with an emphasis on efficacy, safety and tolerability, patient selection, and future directions. Embase and PubMed were searched for relevant terms, and 23 peer-reviewed journal articles presenting primary data on cemiplimab treatment in 5 or more subjects with cutaneous squamous cell carcinoma were included and summarized. Objective response rates in locally advanced and metastatic disease ranged from 42.9% to 50.8% in Phase I/II clinical trials and 32-77% (median 58%) in post-approval observational studies. Phase II trials looking at neoadjuvant use also had favorable response rates. Real-world studies demonstrated cemiplimab efficacy in periorbital tumors, tumors with large caliber perineural invasion, and tumors in solid organ transplant recipients. Cemiplimab was safe and well-tolerated in most patients. While side effects such as fatigue, diarrhea, pruritus, and rash were fairly common, only 9.8% of adverse events required cessation of therapy in phase II trials. Severe adverse events were primarily immune-mediated, including pneumonitis, myocarditis, myositis, and autoimmune hepatitis; the risk of treatment-related death was 3% in clinical trials. Further research on cemiplimab therapy in cutaneous squamous cell carcinoma is needed, and trials are now underway to obtain Phase IV long-term real-world data, further data on adjuvant and neoadjuvant use, and additional data in special populations such as stem cell and solid organ transplant recipients.

Use of immune checkpoint inhibitors (ICIs) in solid organ transplant recipients (SOTRs) with advanced skin cancers presents a significant clinical management dilemma. SOTRs and other immunosuppressed patients have been routinely excluded from ICI clinical trials with good reason: immune checkpoints play an important role in self- and allograft-tolerance and risk of acute allograft rejection reported in retrospective studies affects 10% to 65% of cases. These reports also confirm that cutaneous squamous cell carcinoma and melanoma respond to ICI therapy, although response rates are generally lower than those observed in immunocompetent populations. Prospective trials are now of critical importance in further establishing ICI efficacy and safety. However, based on current knowledge, we recommend that ICIs should be offered to kidney transplant recipients with advanced cutaneous squamous cell carcinoma, melanoma, or Merkel cell carcinoma if surgery and/or radiotherapy have failed. For kidney transplant recipients, this should be first line ahead of chemotherapy and targeted therapies. In SOTRs, the use of ICIs should be carefully considered with the benefits of ICIs versus risks of allograft rejection weighed up on a case-by-case basis as part of shared decision-making with patients. In all cases, parallel management of immunosuppression may be key to ICI responsiveness. We recommend maintaining immunosuppression before ICI initiation with a dual immunosuppressive regimen combining mammalian target of rapamycin inhibitors and either corticosteroids or calcineurin inhibitors. Such modification of immunosuppression must be considered in the context of allograft risk (both rejection and also its subsequent treatment) and risk of tumor progression. Ultimately, a multidisciplinary approach should underpin all clinical decision-making in this challenging scenario.

Preclinical models have demonstrated that PD-1 and its ligand programmed death ligand1 (PD-L1) play significant roles in both graft induction and the maintenance of immune tolerance. It has also been suggested that PD-L1 tissue expression may predict graft rejection; however, the available data are sparse and inconclusive. Some studies were conducted on patients with cancer; most of them do not concern the liver, especially within the context of the use of immunohistochemical tests. Therefore, the aim of our study was to assess the relationship between tissue expression of PD-L1 in a unique material, i.e., in the liver biopsies of pediatric patients after transplantation with the presence of acute cellular rejection (ACR).

This retrospective study enrolled 55 biopsies from 55 patients who underwent protocol liver biopsies. The control group consisted of 19 biopsies from 13 patients diagnosed with acute cellular rejection (rejection activity index/RAI/ from 2 to 8). An immunohistochemical (IHC) staining for PD-L1 was performed in all of the liver specimens; its expression was analyzed in different regions of liver tissue (in inflammatory infiltrates and within the endothelium and hepatocytes). The following changes were re-evaluated in each specimen: features of any kind of rejection (acute cellular, antibody-mediated, chronic); the presence and severity of fibrosis (Ishak scale); and the presence of cholestasis and steatosis. Clinical parameters were also evaluated, including tests of liver function (AST, ALT, GGT, bilirubin).

The age of patients in the study group ranged from 2.37 to 18.9 years (median 13.87 years), with the time after transplantation being 1-17 years (median 8.36 years). The age of patients in the control group ranged from 1.48 to 17.51 years (median 7.93 years), with their biopsies being taken 0.62-14.39 years (median 1.33 years) after transplantation. We found a statistically significant relationship between PD-L1 expression on inflammatory infiltrates and ACR; however, there was no statistically significant relationship between PD-L1 endothelial expression and ACR. PD-L1 was not positive in the hepatocytes regardless of if it was the study or control group that was under observation.

PD-L1 appears to be a promising marker to predict graft rejection.

In this debate, the authors consider whether patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis are candidates for liver transplantation (LT). The argument for LT in this context is based on the premise that, following successful downstaging treatment, LT confers a much greater clinical benefit in terms of survival outcomes than the available alternative (palliative systemic therapy). A major argument against relates to limitations in the quality of evidence for LT in this setting - in relation to study design, as well as heterogeneity in patient characteristics and downstaging protocols. While acknowledging the superior outcomes offered by LT for patients with portal vein tumour thrombosis, the counterargument is that expected survival in such patients is still below accepted thresholds for LT and, indeed, the levels achieved for other patients who receive transplants beyond the Milan criteria. Based on the available evidence, it seems too early for consensus guidelines to recommend such an approach, however, it is hoped that with higher quality evidence and standardised downstaging protocols, LT may soon be more widely indicated, including for this population with high unmet clinical need.

Post-transplant lymphoproliferative disorder (PTLD) is a leading cause of cancer death in solid organ transplant recipients (SOTRs). Relapsed or refractory (R/R) PTLD portends a high risk of death and effective management is not well established. CD19-targeted CAR-T cell therapy has been utilized, but the risks and benefits are unknown. We report the first case of diffuse large B-cell lymphoma (DLBCL) PTLD treated with lisocabtagene maraleucel and present a systematic literature review of SOTRs with PTLD treated with CD19 CAR-T therapy. Our patient achieved a complete response (CR) with limited toxicity but experienced a CD19+ relapse 8 months after infusion despite CAR-T persistence. Literature review revealed 14 DLBCL and 2 Burkitt lymphoma PTLD cases treated with CD19 CAR-T cells. Kidney (n = 12), liver (n = 2), heart (n = 2), and pancreas after kidney (n = 1) transplant recipients were analyzed. The objective response rate (ORR) was 82.4% (14/17), with 58.5% (10/17) CRs and a 6.5-month median duration of response. Among kidney transplant recipients, the ORR was 91.7% (11/12). Allograft rejection occurred in 23.5% (4/17). No graft failure occurred. Our analysis suggests that CD19 CAR-T therapy offers short-term effectiveness and manageable toxicity in SOTRs with R/R PTLD. Further investigation through larger datasets and prospective study is needed.

The development of immune checkpoint inhibitor (ICI) immunotherapy has revolutionized the treatment of several cancers. Malignancies are one of the leading causes of death in solid organ transplant recipients (SOTRs). Although ICI treatment may be an effective option in treating malignancies in SOTRs, concerns about triggering allograft rejection have been raised in this population. Herein, we will review currently available data regarding patients, allograft and malignancy outcomes in SOTRs who received ICI therapy.

Cancer incidence is three to five-fold higher among SOTRs, compared with the general population. Skin cancer is the most prevalent cancer after transplant, followed by kidney cancer, lymphoma and Kaposi sarcoma. There are no large prospective studies evaluating ICI therapy's use for treating cancers in SOTRs. However, retrospective studies have shown that ICI treatment may be associated with improved malignancy outcomes and overall survival (OS). However, the risk of allograft rejection is high (around 40%) of whom about half lose their allograft. Maintaining higher levels of immunosuppression may be associated with a lower risk of allograft rejection, but potentially worse malignancy outcomes.

Although ICI treatment may be associated with improved patient and malignancy outcomes, the risk of allograft rejection and loss are high. Prospective studies are needed to confirm the benefits of ICI therapy in SOTRs and to evaluate the optimal immunosuppression regimen modifications, if any, to improve patient, malignancy and allograft outcomes in transplant recipients.

Cutaneous squamous cell carcinoma (cSCC) is the most common malignancy in immune-suppressed organ transplant recipients (OTRs). Whilst rates of other malignancies (both cutaneous and non-cutaneous) are elevated in this population, the increase is far less striking. This suggests that cSCC must be a highly immunogenic tumor. The tumor immune microenvironment is altered in cSCC from OTRs. It has reduced anti-tumor properties and instead provides an environment that facilitates tumor growth and survival. Understanding the composition and function of the tumor immune microenvironment in cSCC from OTRs is useful for prognostication and therapeutic decisions.

Villitis of unknown etiology (VUE) is an inflammatory disease characterized by the infiltration of maternal CD8 +T cells into the placental villi. Although the pathogenesis of VUE is still debated, dysregulation of the immune system appears to be an important factor in the development of the disease. Interaction of maternal T cells with the fetal antigens seems to be the trigger for the VUE onset. In this context, graft vs host disease (GVHD) and allographic rejection seem to share similarities in the VUE immunopathological mechanism, especially those related to immunoregulation. In this review, we compared the immunological characteristics of VUE with allograft rejection, and GVHD favoring a better knowledge of VUE pathogenesis that may contribute to VUE therapeutics strategies in the future.

International variations in the rates of kidney cancer (KC) are considerable. An understanding of the risk factors for KC development is necessary to generate opportunities to reduce its incidence through prevention and surveillance.

To retrieve and summarize global incidence and mortality rates of KC and risk factors associated with its development, and to describe known familial syndromes and genetic alterations that represent biologic risk factors.

A systematic review was conducted via Medline (PubMed) and Scopus to include meta-analyses, reviews, and original studies regarding renal cell carcinoma, epidemiology, and risk factors.

Our narrative review provides a detailed analysis of KC incidence and mortality, with significant variations across time, geography, and sex. In particular, while KC incidence has continued to increase, mortality models have leveled off. Among the many risk factors, hypertension, obesity, and smoking are the most well established. The emergence of new genetic data coupled with observational data allows for integrated management and surveillance strategies for KC care.

KC incidence and mortality rates vary significantly by geography, sex, and age. Associations of the development of KC with modifiable and fixed risk factors such as obesity, hypertension, smoking, and chronic kidney disease (CKD)/end-stage kidney disease (ESKD) are well described. Recent advances in the genetic characterization of these cancers have led to a better understanding of the germline and somatic mutations that predispose patients to KC development, with potential for identification of therapeutic targets that may improve outcomes for these at-risk patients.

We reviewed evidence on the occurrence of kidney cancer (KC) around the world. Currently, the main avoidable causes are smoking, obesity, and high blood pressure. Although other risk factors also contribute, prevention and treatment of these three factors provide the best opportunities to reduce the risk of developing KC at present.

Transplant onconephrology is a growing specialty focused on the health care of kidney transplant recipients with cancer. Given the complexities associated with the care of transplant patients, along with the advent of novel cancer therapies such as immune checkpoint inhibitors and chimeric antigen-receptor T cells, there is a dire need for the subspecialty of transplant onconephrology. The management of cancer in the setting of kidney transplantation is best accomplished by a multidisciplinary team, including transplant nephrologists, oncologists, and patients. This review addresses the current state and future opportunities for transplant onconephrology, including the roles of the multidisciplinary team, and related scientific and clinical knowledge.

Kidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. Non-melanoma skin cancer has an excess risk of approximately 250 times higher than the general population. Moreover, in solid organ transplant recipients (SOTR) these cancers have a more aggressive behavior, with an increased risk of metastasis and death. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Cemiplimab has therefore been approved since 2018 for the treatment of advanced cSCC. However, data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce and based on published case reports and small case series. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC.

To report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium.

Seven patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. Three patients were on corticosteroid monotherapy, one patient on tacrolimus monotherapy and three patients were on at least 2 immunosuppressants at start of cemiplimab. The ORR was 42.8%, stable disease was seen in 14.3% and progressive disease was found in 42.8% of the patients, respectively. The median administered number of cycles was 12, interquartile range (IQR) 25-75 [3.5 - 13.5]. All patients were treated with surgery before administration of cemiplimab, 71.4% received additional radiotherapy and only 1 patient was treated with chemotherapy prior to receiving cemiplimab. Biopsy-proven acute renal allograft rejection was observed in one patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in one patient of the cohort.

The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to previous surgery, chemo - and/or radiotherapy treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance.

Cancer immunotherapy represents a giant leap forward in the management of malignant diseases. An optimal anti-tumor immune response requires cancer antigen recognition by T-cells followed by an effector immune response. Suppression of T-cell activation prevents cancer cell clearance resulting in tumor proliferation. Recent clinical successes of immune checkpoint inhibitors and chimeric antigen receptor T cell therapies has transformed the landscape of cancer immunotherapy. The goal of immunotherapy is to boost host-protective anti-tumor immunity without concomitantly causing immune-related adverse events. However, immunotherapies can cause multiorgan dysfunction including acute kidney injury. Prompt recognition and management of immunotherapy-associated kidney injury is critical in preserving kidney function and improving patient outcomes.

Programmed cell death-1 (PD-1) inhibitors represent an effective treatment option for advanced cutaneous squamous cell carcinoma (cSCC). However, solid organ transplant (SOT) recipients with cSCC have traditionally been excluded from clinical trials.

To assess the safety and efficacy of PD-1 inhibitors for stage III-IV cSCC in SOT recipients.

A systematic review was performed using the PubMed, EMBASE, and Scopus databases.

We identified 21 articles describing 33 SOT recipients (26 kidney, four liver, two lung, and one heart) with stage III-IV cSCC treated with PD-1 inhibitors. Eleven patients (33.3%) experienced allograft rejection. Of the 25 cases with iRECIST scores, twelve patients (48.0%) had a complete response (CR), eight (32.0%) showed a partial response (PR), three (12.0%) progressive disease, and two (8.0%) stable disease (SD). Including patients without available iRECIST scores, 21 patients (63.6%) showed tumor response. Eleven patients died, with six (50.0%) due to tumor progression and one (11.1%) due to allograft rejection after foregoing dialysis.

PD-1 inhibitors demonstrate efficacy for advanced cSCC and confer a risk of allograft rejection in SOT recipients, requiring careful assessment of risks and benefits. If anti-PD-1 therapy is pursued, use of mTOR inhibitors, prophylactic steroids, and donor-derived cell-free DNA monitoring may mitigate the risk of rejection.

The calcineurin inhibitor-FK506-is a first-line immunosuppressant that regulates T-cell secretion of IL-2 and other cytokines. However, the mechanism of its protective effect on target cells and its role on tumor recurrence and interaction with anti-tumor immune checkpoint inhibitors, such as PD-L1 blocking, are still unclear. Here, in a murine heart transplantation model, we observed the upregulation of programmed death-ligand 1 (PD-L1) expression by FK506 in both dendritic cells (DCs) and allografts. Blocking PD-L1 during FK506 treatment increased IFN-γ and TNF-α expression, enhanced CD4⁺ and CD8⁺ T-cell proliferation, and suppressed Treg differentiation. Moreover, PD-L1 decreased T-cell infiltration and induced T cell apoptosis in both the spleen and graft. PD-L1 was not only required in FK506-mediated immunosuppression but also upregulated by FK506. Treatment with SAFit2, a FKBP51 selective inhibitor, reduced the expression of PD-L1 on DCs and the grafts and interfered with the immunosuppressive effect of FK506, suggesting that the mechanism depends on FK506-binding protein (FKBP) 51 expression. Overall, our results add new insights into the role of FK506, not only on T-cell cytokine secretion but also on co-inhibitory molecular regulation and target cell immune privilege.