PD-1 inhibitor as bridge therapy to liver transplantation?

Abstract

To the Editor: The use of antiprogrammed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) checkpoint inhibitors in the treatment of cancer has rapidly increased and is approved to treat hepatocellular carcinoma (HCC). PD-1 blockade has been discouraged in transplant candidates and recipients due to reports of severe rejection and graft loss.1Abdel-Wahab N Shah M Suarez-Almazor ME et al.Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports.PLoS One. 2016; 11 (e0160221.)Crossref PubMed Scopus (312) Google Scholar, 2Wang DY Johnson DB Davis EJ. Toxicities associated with PD-1/PD-L1 blockade.Cancer J. 2018; 24: 36-40Crossref PubMed Scopus (55) Google Scholar, 3Nordness MF Hamel S Godfrey CM et al.Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: are checkpoint inhibitors safe for the pretransplant patient?.Am J Transplant. 2020; 20: 879-883Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar The clinical outcome of patients receiving immunotherapy before transplant, however, remains unknown. Between 2017 and 2020, nine patients with HCC were listed and successfully transplanted at a single center after receiving nivolumab as an element of pretransplant tumor treatment (Table 1). The mean age was 57 years; 67% were male. The most common underlying liver disease was hepatitis B (56%). Five patients (56%) had prior HCC resection at a median interval of 7 years; one transplant (11%) was from a living donor. Nivolumab was administered at a dosage of 240 mg every 2 weeks. Eight (89%) patients received their last dose within 4 weeks of transplant. Initial immunosuppression was with steroids—an initial dose of 500 mg methylprednisolone tapered to prednisone 10 mg/day over 2 weeks—together with mycophenolate mofetil 1 g twice a day and tacrolimus to maintain a level of 10–12 ng/ml. At a median follow-up of 16 months (range, 8–23 months) posttranplant, no severe allograft rejections/losses, tumor recurrences, or deaths occurred. One patient developed mild acute rejection secondary to low tacrolimus level (<6 ng/ml) and responded rapidly to increased dosage. Explant pathology revealed near complete (>90%) tumor necrosis in one third of the cases.TABLE 1Characteristics of the patientsNo.AgeGenderULDMax tumor diameter (cm)Max pre-LT AFPNo. of LRTSalvage/type transplantationPathology Milan in/outCyclesNivolumab (days pre-LT)PRBC (U)Duration of follow-up post LT (months)ComplicationRejectionRecurrence169MNone1032Yes/LDLTMilan out within UCSF2118023NoneNoneNone256FHCV5.44.42No/DDLTMilan out within UCSF8221422NoneNoneNone358MHBV219.46Yes/DDLTMilan in3213022NoneNoneNone463MHCV, HIV4.45077No/DDLTMilan in421521NoneNoneNone530MHBV3.214932Yes/DDLTMilan in2522016NoneMild (low tacrolimus level)None663MHBV, HIV21580No/DDLTMilan in413114Bile leakNoneNone766MHBV2.54792Yes/DDLTMilan in9253714NoneNoneNone855FHBV2.88203No/DDLTMilan in12708NoneNoneNone953FNASH8.71241Yes/DDLTMilan out within UCSF230178NoneNoneNoneAbbreviations: AFP, alpha-fetoprotein (ng/ml); Age, at transplantation; Cycles, number of nivolumab cycles; DDLT, deceased donor liver transplantation; HBV, hepatitis B; HCV, hepatitis C; HIV, human immunodeficiency virus; LDLT, living donor liver transplantation; LRT, locoregional therapies (chemo/radioembolization, ablation, radiation); LT, liver transplantation; Max tumor diameter, diameter of largest single tumor; Milan criteria, single HCC ≤ 5 cm or up to 3 nodules ≤3 cm; U, units; UCSF criteria, a maximum tumor size of 6.5 cm or 2 lesions ≤4.5 cm in diameter with a total tumor diameter of ≤8 cm; ULD, underlying liver disease. Open table in a new tab Abbreviations: AFP, alpha-fetoprotein (ng/ml); Age, at transplantation; Cycles, number of nivolumab cycles; DDLT, deceased donor liver transplantation; HBV, hepatitis B; HCV, hepatitis C; HIV, human immunodeficiency virus; LDLT, living donor liver transplantation; LRT, locoregional therapies (chemo/radioembolization, ablation, radiation); LT, liver transplantation; Max tumor diameter, diameter of largest single tumor; Milan criteria, single HCC ≤ 5 cm or up to 3 nodules ≤3 cm; U, units; UCSF criteria, a maximum tumor size of 6.5 cm or 2 lesions ≤4.5 cm in diameter with a total tumor diameter of ≤8 cm; ULD, underlying liver disease. In cancer patients, the serum half-life of nivolumab is approximately 27 days; binding of nivolumab to T cell receptors is reversible, lasting not longer than 1 day.1Abdel-Wahab N Shah M Suarez-Almazor ME et al.Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports.PLoS One. 2016; 11 (e0160221.)Crossref PubMed Scopus (312) Google Scholar, 2Wang DY Johnson DB Davis EJ. Toxicities associated with PD-1/PD-L1 blockade.Cancer J. 2018; 24: 36-40Crossref PubMed Scopus (55) Google Scholar, 3Nordness MF Hamel S Godfrey CM et al.Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: are checkpoint inhibitors safe for the pretransplant patient?.Am J Transplant. 2020; 20: 879-883Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 4Munker S De Toni E. Use of checkpoint inhibitors in liver transplant recipients.United European Gastroenterol J. 2018; 6 (Published online 2018 Apr 30.): 970-973Crossref PubMed Scopus (69) Google Scholar The substantial transfusion requirement during transplantation may result in acute clearance of a proportion of the serum nivolumab, accelerating elimination of the drug and its effects. The biological effects of nivolumab on T cell function may be prolonged, and reliance on intraoperative blood loss should not be considered an appropriate strategy. Over half of the cases received less than 7 units in total. Most reported anti-PD-1 treatment after transplant is in kidney recipients to treat advanced cancer; liver is less-prone than kidney to clinically significant rejection. Kittai et al. hypothesized factors that affect safety in this patient population.4Munker S De Toni E. Use of checkpoint inhibitors in liver transplant recipients.United European Gastroenterol J. 2018; 6 (Published online 2018 Apr 30.): 970-973Crossref PubMed Scopus (69) Google Scholar These include the integral role of the PD-1 pathway (increased risk) compared with the CTLA-4 pathway in organ acceptance, sequential implementation of different immune checkpoint inhibitor classes, length of time (decreased risk with time) with a transplant before therapy, intensity of immunosuppressive agents to prevent organ transplant rejection, and immunogenicity of the particular organ grafted.5Kittai AS Oldham H Cetnar J et al.Immune checkpoint inhibitors in organ transplant patients.J Immunother. 2017; 40: 277-281Crossref PubMed Scopus (97) Google Scholar Significant PD-L1 expression in donor allografts may indicate a subclinical alloimmune response and identify patients at high risk of rejection.3Nordness MF Hamel S Godfrey CM et al.Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: are checkpoint inhibitors safe for the pretransplant patient?.Am J Transplant. 2020; 20: 879-883Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar We acknowledge that the heterogeneity of this study makes it difficult to establish guidelines in every day clinical practice. Our results however are a basis for optimism and further investigation of these agents in the pretransplant setting. More research is needed to explore the safety and efficacy of immune checkpoint inhibitors in the setting of organ transplantation. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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