|  6:27 AM (11 hours ago) |
Recently, immune checkpoint inhibitors are becoming one of the key agents of systemic treatment of cancer. The anti-cancer mechanism of this type of agent is totally different from that of conventional therapies; blockade of regulatory receptors and ligand of immune checkpoint molecules arose anti-tumor immunity with durable response. However, owing to its unique action to host immune system, immune checkpoint inhibitors sometimes induce immune-related adverse events (irAEs) which has not been observed for conventional chemotherapies. It has been reported that irAEs are manageable by discontinuation of immune checkpoint inhibitors and corticosteroid. However, severe irAEs might lead to the unsuccessful management of cancer treatment. It is conceivable that irAEs during the treatment of immune checkpoint blockade might mimic the autoimmune disease of the specific organ, such as autoimmune hepatitis (AIH). However, detail of the pathogenesis of irAEs has not been well estimated. In this review, we specially focused on this important issue and discussed the liver toxicity of this type of agent in the context of comparison of clinical and pathological findings of liver damage related to irAEs and AIH.
IntroductionImmune checkpoint inhibitors exert anti-tumor effect by blocking the interaction between regulatory receptors and ligand of checkpoint molecules on T cells, antigen-resenting cells and tumor cells [1]. These are expected to restore the anti-cancer immunity and are becoming one of the key agents for the treatment of cancers [2, 3, 4]. Currently, anti-programmed cell death (PD)-1, anti-PD-ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte associated antigen (CTLA-4) antibodies are available for several types of malignancies, including melanoma, renal cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma, cervical cancer, and gastric cancer. In addition, combination therapies of immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 combination, are approved for the treatment of advanced melanoma, and under clinical trials for many types of cancers [5, 6].
On the other hand, owing to the unique action of immune checkpoint inhibitors on immune system, this type of agent causes immune-related adverse events (irAEs) that mainly involve digestive system, lung, skin, endocrine glands, liver but can potentially affect any tissue. So far, it has been reported that irAEs caused by immune checkpoint monotherapies were manageable under steroid therapy and/or discontinuation of the agent [7, 8, 9, 10]. However, it should be noted that irAEs induced by combination therapies, that aim to enhance the anti-tumor response, have not been well estimated [11, 12, 13].
It has been suspected that irAEs mimic the autoimmune disorders that target specific organs in terms of its pathogenesis. However, recent reports suggested that irAEs could represent a different feature compared to the autoimmune disorders [14]. In this review, we focused on the liver damage induced by immune checkpoint inhibitors and discussed the similarity and difference of clinical and pathological feature between irAEs of liver and autoimmune hepatitis (AIH).
Frequencies of liver damage in the treatment with immune checkpoint inhibitors
Agent (dose per infusion) | Tumor type | Number of the patients | Incidence of liver damage (%) | References | |
Total | Grade ¾ | ||||
Anti-PD-1 antibody | |||||
Pembrolizumab (10 mg/kg) | Melanoma | 277 | 1.8 | 1.8 | Robert et al. [19] |
Nivolumab (3 mg/kg) | Melanoma | 313 | 3.8 | 1.3 | Larken et al. [18] |
Nivolumab (3 mg/kg) | Melanoma | 313 | 4 | 1 | Wolchok et al. [23] |
Nivolumab (3 mg/kg) | Melanoma | 452 | 6.2 | 1.1 | Weber et al. [20] |
Nivolumaba | HCC | 48 | 15 | 6 | El-Khoueiry et al. [28] |
Pembrolizumabb | HCC | 104 | 9 | 4 | Zhu et al. [29] |
Anti-CTLA-4 antibody | |||||
Ipilimumab (3 mg/kg) | Melanoma | 256 | 1.2 | 0.4 | Robert et al. [19] |
Ipilimumab (3 mg/kg) | Melanoma | 311 | 3.9 | 1.6 | Larken et al. [18] |
Ipilimumab (3 mg/kg) | Melanoma | 311 | 4 | 2 | Wolchok et al. [23] |
Ipilimumab (10 mg/kg) | Melanoma | 453 | 14.6 | 5.7 | Weber et al. [20] |
Tremelimumab (15 mg/kg)c | HCC | 20 | 55 | 25 | Sangro et al. [30] |
Anti-PD-1 + anti-CTLA-4 antibodies | |||||
Nivolumab + ipilimumabd | Melanoma | 53 | 21 | 11 | Wolchok et al. [22] |
Nivolumab + ipilimumabe | Melanoma | 313 | 17.6 | 8.3 | Larken et al [18] |
Nivolumab + ipilimumabe | Melanoma | 313 | 19 | 9 | Wolchok et al. [23] |
For the trial on melanoma, cases positive for hepatitis B (HBV) and hepatitis C virus, (HCV) were excluded
aNivolumab 0.1–10 mg/kg. Among 48 patients, 15 and 10 were positive for HBV and HCV, respectively
bPembrolizumab 200 mg
cNivolumab 0.1–10 mg/kg. All patients showed chronic HCV infection
dNivolumab 0.3–3 mg/kg + ipilimumab 1–3 mg/kg
eNivolumab 1 mg/kg + ipilimumab 3 mg/kg
On the other hand, several systemic therapies are found to be effective in advanced HCC cases [24, 25, 26, 27] and several critical trials of immune checkpoint inhibitors are ongoing [28, 29]. Although number of the patients treated with this type of agents is much smaller in HCC than in melanoma cases, liver damage is more frequently observed in HCC cases, where 9–15% of the cases showed increase of ALT, and grade 3/4 toxicity was observed in 4–6% for anti-PD-1 treatment [28, 29]. Furthermore, anti-CTLA-4 antibody, tremelimumab, induced liver damage in 55% for all grades and 25% for grade 3/4 toxicity in the HCC patients, respectively [30]. Therefore, increase of ALT should be carefully monitored during the treatment of immune checkpoint inhibitors in HCC cases, although all liver damages were manageable by discontinuation of the agent and corticosteroid. On the other hand, grade 3/4 liver damage was much more severe for the combination of anti-PD-1 and anti-CTLA4 antibodies: 17.6–21% for all grades and 8.3–11% for grade 3/4 toxicity in melanoma cases [18, 21, 22, 23].
Differences of histological features between AIH and liver damage of irAEs have also been described. Histology of the liver related to irAEs is heterogeneous that should be attributed to the complexity of pathogenesis, including lobular hepatitis, steatosis and steatohepatitis, as well as bile duct injury [32, 33]. In addition to the autoimmune-like hepatitis in liver parenchyma [34], damage in ductal and endothelial cells is observed, suggesting that cellular rejection may be induced by this type of agent; the cases with liver allograft failure have been reported in association with immune checkpoint inhibitors [35, 36, 37].
Liver parenchymal damage induced by anti-PD-1 antibody is mainly represented lobular hepatitis with mild lobular infiltration [38]. It may be accompanied by cholangiolitis, bile duct injury and endothelialitis [14, 38, 39]; although the degree of liver injury was milder compared to that induced by anti-CTLA-4 antibody. Portal fibrosis was also reported for liver injury related to anti-PD-1 antibody. However, infiltration of plasma cell and lymphoid follicles, which was one of the characteristic findings of AIH, was rarely observed [31, 38, 40]. On the other hand, bile duct injury during the treatment using anti-PD-1 antibody may lead to vanishing bile duct syndrome that is attributed to lymphocytic cholangitis [32, 41, 42]. Reportedly, extrahepatic bile duct could also be involved, which represented dilatation of extrahepatic biliary [32]. Elevation of alkaline phosphatase, γ-glutamyl transpeptidase and bilirubin are predominant laboratory findings in the cases with cholangiopathy [43].
Liver injury related to anti-CTLA-4 antibody and its combination with anti-PD-1 antibody could be more severe and, reportedly, represented unique pathological features. The liver injury induced by anti-CTLA-4 may occur earlier than that induced by anti-PD-1 antibody [31]. Most patients showed pan-lobular hepatitis with infiltration of lymphocyte and histiocytes. The infiltrated T lymphocyte mainly represented CD8+ in anti-CTLA-4 antibody-related liver injury, although both CD4+ and CD8+ T lymphocytes were observed in AIH as well as liver injury related to anti-PD-1 antibody [31, 44]. The centrilobular hepatitis, which had been described in AIH, could also be observed in anti-CTLA-4 related liver injury. Bile duct injury and steatohepatitis might take place, but not characteristic findings [31, 44]. In many cases, central vein endothelialitis and sinusoidal distribution of macrophage were reportedly detected. Everett et al. reported two cases of the fibrin ring granulomas in patients with liver damage related to ipilimumab and nivolumab combination therapy, which could be observed in a variety of liver injuries, such as induced by infectious and toxic agents [45]. It generally consists of several layers with a central lipid vacuole surrounded by macrophages, histiocytes and fibrin ring. De Martin et al. also reported that granulomatous hepatitis with fibrin deposit accompanied by severe lobular necrotic and inflammatory activity was frequently detected in the patients treated with anti-PD-1 and anti-CTLA-4 combination [31]. Endothelialitis in central and portal vein also occurred in patients treated with combination therapy [31, 44].
So far, there are no specific predictors that predict emergence of liver damage after the start of immune checkpoint inhibitors. Based on the previous analysis that analyzed 16 cases of liver damage associated with immune checkpoint inhibitors, 9 cases showed positive for ANA or SMA, although their titers are low [31]. Although previous report shows high flare rate of autoimmune disorders in patients with inactive status, risk of liver toxicity in patients with autoimmune liver disease has not been evaluated [33]. In addition, association between the presence of ANA and SMA and risk of emergence of liver damage on the treatment using immune checkpoint inhibitors has not been clarified yet. On the other hand, skin and gastrointestinal complication could be accompanied by liver damage; emergence of such symptom could be a precursor of liver complication [33].
The treatment using immune checkpoint inhibitors is expanding; its liver toxicity is poorly understood [46]. It has been considered that immune checkpoint inhibitors arouse autoimmune reaction, but clinical and pathological feature of liver injury related to this type of agent is, in some respects, different from that of AIH [14]. The typical serological finding of AIH was not observed in liver injury related to irAEs, where major infiltrating cells are histiocyte and macrophage but not plasma cells. Severe interface hepatitis and rosette formation are rare, and granulomatous lobular hepatitis, fibrin ring granulomas, and endothelialitis and bile duct injury are more frequently observed compared to AIH.
| 欢迎光临 肝胆相照论坛 (http://hbvhbv.info/forum/) | Powered by Discuz! X1.5 |