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Immune checkpoint inhibitors in the cancer patient with an organ transplant

Abstract

The use of immune checkpoint inhibitors (ICI) in several cancers is expanding; however, their use in patients with cancer and an organ transplant is very limited. In this review, we summarize the literature and the experience of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) inhibitors in the organ transplant patient. The immunology of CTLA-4 and PD-1 inhibitors and their role in tolerance breakdown is also reviewed. While CTLA-4 inhibitors have been successfully used in kidney, liver, and heart transplant patients without rejection, the uses of PD-1 inhibitors and the combination therapy of CTLA-4 and PD-1 inhibitors have been associated with cellular- and antibody-mediated rejection. While immunosuppression minimization is needed for ICI to provide the best response when managing transplant patients who develop malignancy, this can lead to rejection episodes. Prevention strategies, such as the use of ongoing steroids and sirolimus, could prevent rejection while sustaining tumor response. As the experience grows with these agents, we will learn more about tolerance and the use of ICI in the organ transplant patient. Therefore, the use of an immune checkpoint blockade in transplantation is extremely difficult, and future research should focus on finding the right balance between unleashing the immune system to provide an anti-tumor effect but at the same time sustaining tolerance so that rejection is suppressed. Also, the ability to identify biomarkers that may predict rejection early and allow for the fine tuning of doses and frequencies of drug administration would be very helpful.

J onco-nephrol 2017; 1(1): 42 - 48

Article Type: REVIEW

DOI:10.5301/jo-n.5000006

Authors

Rimda Wanchoo, Leonardo V. Riella, Nupur N. Uppal, Carlos A. Lopez, Vinay Nair, Craig Devoe, Kenar D. Jhaveri

Article History

Disclosures

Financial support: L.V.R. has received grant support from the American Heart Association (12FTF120070328), Department of Defense (RT150078 and RT150081) and investigator-initiated research grant from Bristol-Meyers-Squibb.
Conflict of interest: R.W. serves as an associate editor for the Journal of Onconephrology (JON) and K.D.J. serves on the scientific advisory board JON. R.W. and K.D.J. are expert members of Cancer and Kidney International Network (CKIN) and K.D.J. serves on the governing body for CKIN.

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Introduction

Immune checkpoint inhibitors (ICI) are now being used in the treatment of several malignancies with great success (1). Cancer surveillance is provided by the immune system, wherein malignant cells detected by the presence of neo-antigens are eliminated in their earliest stages (2). However, tumors escape this process by employing mechanisms to avoid recognition by the immune system or actively suppress anticancer immune responses (3, 4). Enhancing anti-tumor T cell immunity with checkpoint inhibitor antibodies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1) has shown significant clinical benefits in tumor regression and prolonged stabilization of many solid tumors leading to the U.S. Food and Drug Administration’s (FDA) approval for use in non-small cell lung cancer, melanoma, bladder cancer, Hodgkin lymphoma, and renal cell cancer (1).

The immune response is initiated by the antigen-specific signal, which arises from the interaction of the T cell receptor (TCR) with the major histocompatibility complex (MHC) in association with peptide on the antigen-presenting cell (APC). Complementary signals then modulate the fate of this interaction. As an example, the cell surface molecule CD28 delivers a positive co-stimulatory signal to the T cell via interaction with B7 ligands on the APC, enhancing T cell activation. On the contrary, CTLA-4 receptor on the T cell competes for the same B7 ligands and is capable of inhibiting T cell activation, preventing further cytokine secretion, differentiation, and proliferation. Therefore, the CTLA-4 signal serves to put the “brakes” on the immune system. Blocking the CTLA-4 is akin to “taking your foot off the brakes” of the immune system (5). Ipilimumab is a monoclonal antibody that has anti-tumor activity by blocking CTLA-4. The PD-1 receptor is another co-inhibitory signal comprised of a cell surface molecule with a single immunoglobulin super-family domain. PD-1 is expressed on activated T cells, B cells, natural killer T cells, monocytes, and dendritic cells (6-7-8). PD-1 has two ligands, PD-ligand-1 (L1) and ligand-2 (L2). These differ from CTLA-4 ligands in that they are present in both hematopoietic and nonhematopoietic cells while CTLA-4 are primarily expressed on hematopoietic cells only. Interestingly, the tumor expression of PD-L1 is thought to be one of the mechanisms of immune evasion by cancer cells. The role of PD-L2 in cancer immunology is less clear (7, 8). Monoclonal antibodies directed against PD-1 prevent the engagement of PD-1 with its ligands, leading to enhanced T cell stimulation. They assert anti-neoplastic activity by rescuing the T cell from its quiescent state, thus allowing it to regain effector function against tumor cells. PD-1 inhibition is akin to “pressing on the accelerator” of the immune system (6). Nivolumab and pembrolizumab , both monoclonal antibody therapies designed to directly block the interaction between PD-1 and its ligands, have been successfully used in many cancers. Recently, atezolizumab, which is a PD-L1 inhibitor was approved by the FDA for bladder cancer (9). All clinical trials using CTLA-4 and PD-1 inhibitors excluded patients on chronic immunosuppression both for autoimmune disease and organ transplants. However, two recent trials (10, 11) have shown that the use of CTLA-4 inhibitors might be relatively safe in patients with autoimmune diseases, but data on organ transplants are still scarce. Nonetheless, the use of these agents in immunosuppressed patients with refractory cancer is expanding.

Immune checkpoint inhibitors and known renal, hepatic, and cardiac toxicities

While colitis, dermatitis and pneumonitis are the common immune mediated adverse events associated with ICI(5), renal, cardiac and hepatic toxicities are are less frequently observed. Checkpoint inhibitor-related renal toxicity is an immune-mediated process. The incidence of acute kidney injury with both anti CTLA-4 and PD-1 inhibitors in phase 2 and 3 studies is 2%-3% (12). Acute interstitial nephritis (AIN) is the most common biopsy finding reported with PD-1 inhibitors (12, 13), while ipilimumab has been associated with AIN and podocytopathies, such as lupus-like nephritis, minimal change disease, and thrombotic microangiopathy (14). Hyponatremia related to hypophysitis has been reported as well (15). For CTLA-4 antagonists-associated renal injury, the time of onset is 2-3 months in the majority of cases. Most cases of AIN are responsive to steroids if identified early in the course of renal injury, and very few patients have required dialysis. The renal injury related to anti-PD-1 therapy is AIN, which usually appears later, 3-10 months into treatment. Steroids are also effective in the treatment of this immune-mediated adverse effect (12-13-14). When both CTLA-4 and PD-1 inhibitor drugs are combined, granulomatous or diffuse AIN can be found on kidney biopsy with a partial response to steroids (14, 16). A recent review by our group summarizes renal toxicities associated with ICI (14).

Cardiac toxicity is a rare side effect of ICI. The time of onset is variable, but a case of fatal myocarditis has been reported after a single treatment with combination of nivolumab plus ipilumumab (17). The incidence of myocarditis is 0.06% with nivolumab and 0.27% with a combination therapy of nivolumab and ipilumumab (17). Treatment usually involves using intravenous high dose steroids, infliximab and/or intravenous anti-thymocyte globulin.

Elevations in serum levels of the hepatic enzymes, aspartate aminotransferase and alanine aminotransferase can be seen with both CTLA-4 and PD-1 antagonists. Most episodes are asymptomatic laboratory abnormalities. Among patients that develop liver-related toxicities (e.g., hepatitis), the most common time of onset is 2-3 months after the initiation of treatment, although early or delayed events also may be observed (18). The incidence of hepatitis is 5%-8% for both CTLA-4 and PD-1 inhibitors. Hepatotoxicity with the combination therapy of nivolumab and ipilumumab can be as high as 20% (18). Hepatitis may persist for quite some time and may require prolonged or repeated corticosteroid tapers (a minimum of 3 weeks treatment is suggested) and/or additional immunosuppression, such as mycophenolate mofetil or intravenous anti-thymocyte globulin (19). Given the scope of this article, the authors refer the reader to an exhaustive review on all immune-related toxicities associated with ICI by Bertrand et al (20).

Kidney transplant experience

The PD-1 pathway plays a very important role, both in the development of malignancy and in the maintenance of adaptive immune tolerance in patients with solid organ transplants on long-term immunosuppression (21). ICI led to T cell activation, which helps in tumor destruction but can also lead to acute rejection and graft loss. Several cases of acute rejection have been reported where ICI was used in kidney transplant patients (21-22-23-24).

The first reported cases of kidney transplant patients receiving ICI involved two patients with metastatic melanoma who received the CTLA-4 antagonist ipilumumab (25). Renal allografts in both patients were unaffected by ipilumumab, and the patients had excellent anti-tumor response to the immunotherapy. In contrast, 4 cases of renal allograft loss have been associated with nivolumab and pembrolizumab, which are both PD-1 inhibitors (21-22-23-24). Two received PD-1 inhibitor therapy (pembrolizumab and nivolumab) shortly after the CTLA-4 inhibitor ipilimumab (i.e., they received combination treatment with CTLA-4 and a PD-1 inhibitor). Graft loss, which occurred days to weeks following PD-1 inhibitor administration, was due to T-cell-mediated (Banff type IIA or IIB) or cellular- and antibody-mediated acute rejection (21-22-23-24). Herz et al (26) reported the case of a renal transplant patient with baseline creatinine in 1.7mg/dL who received both CTLA-4 and PD-1 inhibitors for metastatic melanoma and did not have a rejection episode. In that particular case, the immunosuppression was not altered and the patient was continued on tacrolimus and prednisone. While graft loss was not observed, the melanoma progressed. One relevant point is related to how the maintenance immunosuppression is managed. Transplant centers may have different approaches with regard to the reduction of immunosuppression after cancer diagnosis, which may interfere with events such as rejection. Pre-clinical studies have suggested the importance of PD-1 and its ligands in influencing allograft adaptive tolerance to transplants (27). The 4 cases of rejection (21-22-23-24) were the first to demonstrate the relevance of the PD-1 pathway in maintaining tolerance in solid organ transplants. Interestingly, these findings suggest the functional difference between CTLA-4 and PD-1; the latter is more important in immunomodulation within peripheral tissues. Based on the 7 cases, it appears that PD-1 inhibitors could be more prone to causing rejection in the transplanted kidney compared to CTLA-4 antagonists, especially when the patients have received anti-CTLA-4 agents prior to PD-1 inhibitor treatment and have limited immunosuppression on board (21-22-23-24-25-26). This may be related to the key regulatory role of PD-1 in preventing allospecific T cells from proliferating and becoming activated in the secondary lymphoid organs. In addition, the blockade of PD-1/PD-L1 interaction may also affect the immune response in the graft itself; for example, by blocking the inhibitory signal from renal tubular cells or endothelium cells to effector T cells (28-29-30-31). This peripheral immune regulatory network plays an essential role in maintaining graft tolerance and minimizing the chance of rejection (27). In a recently published case from our center (32), we presented a novel strategy to prevent rejection in transplant recipients receiving PD-1 inhibitors using pre-emptive steroids and sirolimus. Table I summarizes the 8 published cases of the use of ICI in kidney transplant patients.

Summary of patients on immune check point inhibitors in renal transplantation

Reference Therapy Onset of renal dysfunction Type of cancer Age Sex Renal pathology Renal transplant information Renal outcome Cancer outcome
AKI = acute kidney injury; DDRT = deceased donor renal transplant; LRRT = living related renal transplant; MMF = mycophenolate mofetil; SCC = squamous cell carcinoma.
25 Ipilimumab No AKI with creatinine stable at 1.2 mg/dL Metastatic melanoma 72 Male No biopsy DDRT 2000 (tacrolimus & prednisone) Tacrolimus discontinued Remains stable on agent after 2 years Partial response
25 Ipilimumab No AKI with creatinine stable at 2.0 mg/dL Metastatic melanoma 58 Male No biopsy DDRT 2004 (MMF, tacrolimus, & prednisone) MMF and tacrolimus discontinued Remains stable
32 Nivolumab No AKI Duodenal cancer 70 Male No biopsy LRRT (2010) Tacrolimus changed to sirolimus, and prednisone tapered to prevent rejection No change in renal function 85% response
22 Ipilimumab followed by pembrolizumab 5 weeks after last dose of ipilimumab and 3 weeks following last dose of pembrolizumab presented with AKI and a serum creatinine of 8.7 mg/dL (baseline creatinine 1.1 mg/dL ) Metastatic melanoma 68 Male Mixed cellular active and antibody rejection (BANFF IIA) DDRT 2000 cyclosporine, prednisone Cyclosporine discontinued Steroids and low dose tacrolimus resumed without renal recovery Data not provided
23 Ipilimumab followed by nivolumab 5 weeks after ipilimumab and 1 week after last dose of nivolumab Metastatic melanoma 48 Male Acute cellular rejection BANFF IIA DDRT 2001 (prednisone, tacrolimus) Tacrolimus stopped Started steroids and dialysis No response
21 Pembrolizumab AKI after 8 weeks Squamous cell carcinoma 57 Female Acute cellular rejection DDRT (1989) on prednisone and cyclosporine Cyclosporine discontinued Started dialysis 85% reduction in tumor
24 Nivolumab AKI after 6 weeks Non-small cell lung cancer of lung 75 Male Acute cellular rejection (BANFF IIB) Transplant type not mentioned Cyclosporine prednisone Prednisone and dialysis Data not provided
26 Ipilumumab followed by nivolumab No AKI Metastatic melanoma 77 Male Metastatic melanoma Transplant type not mentioned (2007). Patient was continued on prednisone 5 mg and tacrolimus 2 mg BID Renal function was not altered Progression of disease

Other organ transplant experiences

Table II summarizes 2 cases of liver transplantation and 1 case of a heart transplant where ICI was used successfully without rejection episodes. At the time of ipilimumab treatment, the 2 liver transplant recipients (33, 34) were receiving low dose prednisone, plus very low dose tacrolimus, or low dose sirolimus. One of the liver transplant patients did have a transient rise in liver function but did not have a liver biopsy to investigate rejection (34). The heart transplant patient received ipilimumab followed by pembrolizumab, and tacrolimus was continued (35). The patient had no immune-related adverse events; however, the disease progressed.

Summary of patients on immune check point inhibitors in liver and heart transplant

Reference Therapy History of any prior cancers Type of cancer Age (y) Gender Organ transplant information Graft outcomes Cancer outcome
ALT = alanine aminotransferase; AST = aspartate transaminase.
33 Ipilimumab None Melanoma 59 F Liver transplant No rejection and no graft loss No improvement
34 Ipilumumab None Melanoma 67 M Liver transplant Increased AST and ALT but no biopsy done. No graft loss Tumor shrinkage
35 Ipilumumab followed by pembrolizumab None Melanoma 62 M Heart transplant No rejection or graft loss Progression of disease

Immunology of the transplant recipient on immune checkpoint inhibitors

Co-inhibitory signals play a key role in the regulation of the alloimmune response against the transplanted organ. In general, CTLA-4 signals are dominant in secondary lymphoid organs, where it functions by modulating activation during the initial phase of the immune response, while PD-1 interactions predominate within the peripheral tissues and the tumor micro-environment during the effector phase of a T cell response (36, 37) (Fig. 1). Multiple reports have shown the importance of these signals in transplantation. Blocking CTLA-4 early after transplant precipitates rejection in a murine liver transplant tolerance model in which B10 livers were transplanted into C3H recipients (38). However, the late blockade of CTLA-4, once tolerance has been established, does not affect graft survival (39). Overall, CTLA-4 plays a critical role in alloimmune regulation, in particular in the induction of graft tolerance. In contrast, animal models have demonstrated that an intact PD-1/PD-L interaction is important for both the induction and the maintenance of graft tolerance (31, 40). The blockade of PD-1 and PD-L1 (but not PD-L2) using an antibody approach significantly accelerated cardiac graft rejection in a fully MHC mismatched model, particularly in the absence of CD28 co-stimulation (41). In a fully MHC mismatched cardiac transplant model in which tolerance was induced by a co-stimulation blockade, early administration of an anti-PD-L1 monoclonal antibody prevented tolerance induction, while delayed administration abrogated graft survival (40). Accelerated rejection was associated with a significant increase in the frequency of CD8+ effector memory T cells and interferon (IFN)-γ-producing alloreactive T cells in the periphery, while the Foxp3+-graft infiltrating Tregs decreased (40). In addition, transplant tolerogenic dendritic cells have high PD-L1 expression relative to CD80 and CD86 (co-stimulatory molecules) and may be the key critical component of the tolerance of liver transplantation (42, 43). Furthermore, PD-L1 expression on tubular cells of the kidney have been shown to suppress alloreactive human T cell responses in vitro (44) and protects the tubules against ischemia reperfusion injury (45). Higher PD-L1 tissue expression triggered by IFN-γ release provides a negative feedback look at the immune system, creating a protective shield from human immune attack. Therefore, the blockade of PD-1 may interfere with the suppressive signal that prevent alloreactive T cells from attacking the allograft, leading to a higher risk of both cellular- and antibody-mediated rejection in the 4 cases discussed above (21-22-23-24). Indeed, the absence of a PD-L1 signal on donor grafts prevents tolerance induction in animal transplant models, indicating a critical role of the transplanted organ in down-regulating the alloimmune response (31). In summary, the PD-1/PD-L1 pathway is key for tolerance development and for the maintenance of peripheral immune regulation.

Co-inhibitory signals. (A) CTLA-4 signal may inhibit T cells through multiple mechanisms, including competition with CD28 for B7 ligands, inhibition of intracellular signal downstream from the TCR, internalization of B7 ligands, or the release of indoleamine 2,3-dioxygenase (IDO) by the APC. (B) PD1 signal inhibits T cell by recruiting tyrosine phosphatase SHP-2, which then inactivates PI3K, a critical step in T cell activation. While CTLA-4 signals predominate on secondary lymphoid organs, PD-1 is dominant on the peripheral target tissue, such as tubular epithelial kidney cells. APC = antigen-presenting cell; CTLA-4 = anti-cytotoxic T-lymphocyte-associated protein 4; PD-1 = anti-programmed cell death protein 1; TCR = T cell receptor.

A blockade of CTLA-4 and PD-1 in transplant recipients increases the activation of T cells, not only against malignant cells, but also of T cells with specificity to donor antigens. The unleashing of T cell activation due to a PD-1 blockade may also enhance B cell proliferation and differentiation into antibody-secreting cells, leading to antibody-mediated rejection, especially in the setting of immunosuppression withdrawal. What is unclear to us is why liver and heart transplant patients do not experience severe rejection as seen in renal transplant patients. In addition, there is not enough experience with the use of ICIs in the other organ transplants to make any observations. As the experience grows with the use of these agents in other organ transplants, we will learn more about tolerance and the use of ICI in the organ transplant patient. Therefore, the use of the immune checkpoint blockade in transplantation is extremely difficult and future research should focus on understanding the right balance between unleashing the immune system and the continuation of anti-rejection medications, possibly by identifying biomarkers that may predict rejection early and allow better fine tuning of the doses and frequencies of drug administration.

Prevention

The transplant community should be aware of the potential risk of rejection in kidney transplant recipients with the use of ICI. The close monitoring of kidney function and the moderate reduction of immunosuppression are warranted. The use of rapamycin is an attractive option as it has recently been shown in mice that T-box protein expressed in T-cell-dependent cancer immunosurveillance by tumor-reactive CD8 T cells is profoundly inhibited by cyclosporine but not by rapamycin (46). The conversion of tacrolimus to the mammalian target of rapamycin inhibitors and the increase of prednisone to high doses with a taper over a few months, as suggested by Barnett et al (32), may be a reasonable alternative regimen that might prevent rejection and may not significantly limit the efficacy of CTLA-4 or PD-1 antibodies against cancer (47). This is based on case reports (32, 34); however, more studies are still needed.

Conclusions

ICI therapy that includes a PD-1 inhibitor may be regarded as contraindicated in recipients of life-saving organs, such as liver, heart, and lung. It is possible that the low immunological risk transplant recipient might be able to tolerate these agents better than the high immunological risk patient. At this point, there is not enough data to give specific recommendations. The risk of rejection and graft loss may be reduced by the use of the low dose mammalian target of rapamycin inhibitors along with low dose prednisone as done elegantly in a published case (32). Prospective studies are needed before any recommendation can be made with regard to the management of immunosuppression in transplant recipients receiving checkpoint inhibitor therapy. A close collaboration between oncologists, onconephrologists, and transplant specialists is strongly encouraged when dealing with organ transplant patients requiring immune checkpoint inhibitors.

Disclosures

Financial support: L.V.R. has received grant support from the American Heart Association (12FTF120070328), Department of Defense (RT150078 and RT150081) and investigator-initiated research grant from Bristol-Meyers-Squibb.
Conflict of interest: R.W. serves as an associate editor for the Journal of Onconephrology (JON) and K.D.J. serves on the scientific advisory board JON. R.W. and K.D.J. are expert members of Cancer and Kidney International Network (CKIN) and K.D.J. serves on the governing body for CKIN.
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Authors

Affiliations

  • Division of Nephrology, Section of Onconephrology, Department of Internal Medicine, Hofstra Northwell School of Medicine, Great Neck, NY - USA
  • Renal Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA - USA
  • Division of Nephrology, Department of Internal Medicine, Hofstra Northwell School of Medicine, Great Neck, NY - USA
  • Department of Internal Medicine, Hofstra Northwell School of Medicine, Great Neck, NY - USA
  • Division of Nephrology, Section of Transplantation, Department of Internal Medicine, Hofstra Northwell School of Medicine, Great Neck, NY - USA
  • Division of Hematology/Oncology and the Northwell Cancer Institute, Department of Internal Medicine, Hofstra Northwell School of Medicine, Great Neck, NY - USA

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