Immune checkpoint inhibitors in liver transplant recipients - a review of current literature

Abstract

Immuno-oncology, particularly with the development of immune checkpoint inhibitors (ICIs), has become a front-line category of cancer-directed therapy, including in the treatment of hepatocellular carcinoma (HCC). While liver transplant (LT) offers a potential cure for HCC, the use of ICIs is a topic of safety concern both pre- and post-transplant due to the risk of donor graft rejection. Nonetheless, some scenarios for which the therapeutic effects of ICI may be highly beneficial include the downstaging of unresectable HCC pre-transplant, or the treatment of recurrent HCC and secondary malignancies post-transplant. In this review, we explored the evidence surrounding the use of ICI in the peri-transplant setting, including safety and efficacy. In a comprehensive review of 28 cases of ICI use post-transplant, we found graft rejection in 9 of 28 cases (32%). Some factors that may increase the risk of rejection include younger age, less time between LT and ICI therapy, and PD-1/PD-L1 expression in the donor graft (particularly when using anti-PD-1/anti-PD-L1 ICIs). Despite these concerns, we relay a case of successful HCC downstaging with nivolumab and subsequent LT. We also describe several cases of response to ICIs post-LT (7 of 28 cases) among a group that is often heavily pre-treated. We conclude that ICIs are valuable options in the peri-transplant setting that have demonstrated promising efficacy based on case reports. Controlled clinical trials are needed to further investigate the conditions that may allow safe delivery of these therapies.

Keywords

Immunotherapy / immune checkpoint inhibitors / CTLA-4 inhibitors / PD-1 inhibitors / hepatocellular carcinoma / liver transplant / allograft rejection

References

[1] Kanwal F.Surveillance for hepatocellular carcinoma: current best practice and future direction.Gastroenterology2019;157:54-64 PMCID:PMC6636644

[2] White DL,Kanwal F,El-Serag HB.Incidence of hepatocellular carcinoma in all 50 United States, from 2000 through 2012.Gastroenterology2017;152:812-20.e5 PMCID:PMC5346030

[3] Lucey MR,Ojo L.Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the study of liver diseases and the American Society of transplantation.Liver Transpl2013;19:3-26

[4] Ho CM,Hu RH.Harnessing immunotherapy for liver recipients with hepatocellular carcinoma: a review from a transplant oncology perspective.Ther Adv Med Oncol2019;11:1758835919843463 PMCID:PMC6487770

[5] Kumar V,Rennke HG.The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature.Oncologist2020;25:505-14 PMCID:PMC7288631

[6] Walunas TL,Bakker CY.CTLA-4 can function as a negative regulator of T cell activation.Immunity1994;1:405-13

[7] Hodi FS.Cytotoxic T-lymphocyte-associated antigen-4.Clin Cancer Res2007;13:5238-42

[8] Lubienski A.Hepatocellular carcinoma: interventional bridging to liver transplantation.Transplantation2005;80:S113-9

[9] Cardarelli-Leite L,Klass D.Current locoregional therapies and treatment strategies in hepatocellular carcinoma.Curr Oncol2020;27:S144-51 PMCID:PMC7739520

[10] Llovet JM,Mazzaferro V.SHARP Investigators Study GroupSorafenib in advanced hepatocellular carcinoma.N Engl J Med2008;359:378-90

[11] Network NCC. Hepatobiliary Cancers (Version 5.2020). In. Available from https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. [Last accessed on 1 Jul 2021]

[12] Eilard MS,Naredi P.A prospective clinical trial on sorafenib treatment of hepatocellular carcinoma before liver transplantation.BMC Cancer2019;19:568 PMCID:PMC6560824

[13] Castelli G,Giacomin A.Sorafenib use in the transplant setting.Liver Transpl2014;20:1021-8

[14] Nordness MF,Godfrey CM.Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: are checkpoint inhibitors safe for the pretransplant patient?.Am J Transplant2020;20:879-83

[15] Schwacha-Eipper B,Banz V.Immunotherapy as a downstaging therapy for liver transplantation.Hepatology2020;72:1488-90

[16] El-khoueiry AB,Yau T.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.Lancet2017;389:2492-502 PMCID:PMC7539326

[17] Finn RS,Merle P.KEYNOTE-240 investigatorsPembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial.J Clin Oncol2020;38:193-202

[18] Yau T,Kim TY.Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial.JAMA Oncol2020;6:e204564 PMCID:PMC7530824

[19] Chuzi S,Cruz M.Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor-related pneumonitis.Cancer Manag Res2017;9:207-13 PMCID:PMC5476791

[20] Martins F,Sykiotis GP.Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.Nat Rev Clin Oncol2019;16:563-80

[21] De Martin E,Papouin B.Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors.J Hepatol2018;68:1181-90

[22] Centanni M,Trocóniz IF,van Hasselt JGC.Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors.Clin Pharmacokinet2019;58:835-57 PMCID:PMC6584248

[23] Goldaracena N,Scalera I.Multicenter validation of a score to predict prognosis after the development of HCC recurrence following liver transplantation.HPB (Oxford)2019;21:731-8

[24] Sapisochin G.Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches.Nat Rev Gastroenterol Hepatol2017;14:203-17

[25] Sapisochin G,Astete S.Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a large Euro-American series.Ann Surg Oncol2015;22:2286-94

[26] de'Angelis N,Carra MC.Managements of recurrent hepatocellular carcinoma after liver transplantation: a systematic review.World J Gastroenterol2015;21:11185-98 PMCID:PMC4607916

[27] Zhu AX,Edeline J.Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.Lancet Oncol2018;19:940-52

[28] Finn RS,Ikeda M.IMbrave150 InvestigatorsAtezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med2020;382:1894-905

[29] Green AC.Increased risk of melanoma in organ transplant recipients: systematic review and meta-analysis of cohort studies.Acta Derm Venereol2015;95:923-7

[30] Suresh K,Lin CT.Immune checkpoint immunotherapy for non-small cell lung cancer: benefits and pulmonary toxicities.Chest2018;154:1416-23 PMCID:PMC6335259

[31] Furue M,Wada N,Kadono T.Melanoma and immune checkpoint inhibitors.Curr Oncol Rep2018;20:29

[32] Kumar S.2235 nivolumab-induced severe allograft rejection in recurrent post-transplant hepatocellular carcinoma.Am J Gastroenterol2019;114:S1251

[33] Chen JA,Kim EJ.PD-1 blockade in a liver transplant recipient with microsatellite unstable metastatic colorectal cancer and hepatic impairment.J Natl Compr Canc Netw2019;17:1026-30

[34] Kuo JC,Hogg D.Immune checkpoint inhibitor therapy in a liver transplant recipient with a rare subtype of melanoma: a case report and literature review.Melanoma Res2018;28:61-4

[35] Schvartsman G,Sood G,Tawbi H.Immune checkpoint inhibitor therapy in a liver transplant recipient with melanoma.Ann Intern Med2017;167:361-2

[36] Ranganath HA.Administration of ipilimumab to a liver transplant recipient with unresectable metastatic melanoma.J Immunother2015;38:211

[37] Gomez P,Zucker K.A case of hepatocellular carcinoma (HCC) immunotherapy inducing liver transplant rejection: 2416.Am J Gastroenterol2018;113:S1347

[38] Anugwom C.Nivolumab-induced autoimmune-like cholestatic hepatitis in a liver transplant recipient.ACG Case Rep J2020;7:e00416 PMCID:PMC7363460

[39] Varkaris A,Nugent FW.Preserved liver transplant after PD-1 pathway inhibitor for hepatocellular carcinoma.Am J Gastroenterol2017;112:1895-6

[40] Friend BD,McDiarmid SV.Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma.Pediatr Blood Cancer2017;64:e26682

[41] Rammohan A,Farouk M,Rela M.Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: the silver bullet?.Hepatology2018;67:1166-8

[42] Amjad W,Gupta A,Liu L.Successful treatment of disseminated hepatocellular carcinoma after liver transplantation with nivolumab.J Clin Exp Hepatol2020;10:185-7 PMCID:PMC7067990

[43] DeLeon TT,Aqel BA.Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience.J Gastrointest Oncol2018;9:1054-62 PMCID:PMC6286929

[44] Morales RE,Walsh MM,Lipson EJ.Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation.J Immunother Cancer2015;3:22 PMCID:PMC4469313

[45] Gassmann D,Mertens JC.Liver allograft failure after nivolumab treatment-a case report with systematic literature research.Transplant Direct2018;4:e376 PMCID:PMC6092180

[46] Toni EN, Gerbes AL. Tapering of immunosuppression and sustained treatment with nivolumab in a liver transplant recipient.Gastroenterology2017;152:1631-3

[47] Dueland S,Boberg KM.Acute liver graft rejection after ipilimumab therapy.Ann Oncol2017;28:2619-20

[48] Biondani P,Samuel D.Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient.Ann Oncol2018;29:286-7

[49] Lee BT,Chopra S,Han HH.Checkpoint inhibitor-induced rejection of a liver allograft: a combination of acute T cell-mediated and antibody-mediated rejection.Liver Transpl2019;25:1845-8

[50] Jarroudi O, Ulusakarya A, Almohamad W, Afqir S, Morere JF. Anti-programmed cell death Protein 1 (PD-1) immunotherapy for metastatic hepatocellular carcinoma after liver transplantation: a report of three cases.Cureus2020;12:e11150 PMCID:PMC7586420

[51] Robert C,Schachter J.Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.Lancet Oncol2019;20:1239-51

[52] Robert C,Brady B.Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med2015;372:320-30

[53] Brahmer JR,Schneider BJ.National Comprehensive Cancer NetworkManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline.J Clin Oncol2018;36:1714-68 PMCID:PMC6481621

[54] Yau T,Finn RS.CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC).Ann Oncol2019;30:v874-v5

[55] Wainberg ZA,Jaeger D.Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC).J Clin Oncol2017;35:4071

[56] Yau T,Kim TY.Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.J Clin Oncol2019;37:4012

[57] Freites-Martinez A,Arias-Santiago S.Using the common terminology criteria for adverse events (CTCAE - Version 5.0) to evaluate the severity of adverse events of anticancer therapies.Actas Dermosifiliogr (Engl Ed)2021;112:90-2

[58] Larkin J,Wolchok JD.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med2015;373:1270-1

[59] Horvat TZ,Dang TO.Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial sloan kettering cancer center.J Clin Oncol2015;33:3193-8 PMCID:PMC5087335

[60] Ziemer M,Beyer S,Berg T.Managing immune checkpoint-inhibitor-induced severe autoimmune-like hepatitis by liver-directed topical steroids.J Hepatol2017;66:657-9

[61] Kittai AS,Cetnar J.Immune checkpoint inhibitors in organ transplant patients.J Immunother2017;40:277-81

[62] Ono Y,Nakao T.Graft-infiltrating PD-L1(hi) cross-dressed dendritic cells regulate antidonor T cell responses in mouse liver transplant tolerance.Hepatology2018;67:1499-515 PMCID:PMC5856603

[63] Demetris AJ,Hübscher SG.2016 comprehensive update of the banff working group on liver allograft pathology: introduction of antibody-mediated rejection.Am J Transplant2016;16:2816-35

[64] Wang L,Hancock WW.Programmed cell death 1 (PD-1) and its ligand PD-L1 are required for allograft tolerance.Eur J Immunol2007;37:2983-90

[65] Ma D,Li Y.PD-L1 Deficiency within islets reduces allograft survival in mice.PLoS One2016;11:e0152087 PMCID:PMC4798758

[66] d'Izarny-Gargas T,Zaidan M.Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: a systematic review.Am J Transplant2020;20:2457-65

[67] Hartmann EL. Renal Transplantation in the older adult. In. Geriatric Nephrology Curriculum. American society of nephrology; 2009. Available from: https://www.asn-online.org/education/distancelearning/curricula/geriatrics/Chapter24.pdf [Last accessed on 11 Jun 2021]

[68] Dogan N,Schmidt HH,Beckebaum S.Acute allograft rejection in liver transplant recipients: incidence, risk factors, treatment success, and impact on graft failure.J Int Med Res2018;46:3979-90 PMCID:PMC6136012

[69] Durand F,Cauchy F,Soubrane O.Age and liver transplantation.J Hepatol2019;70:745-58

[70] Fisher J,Fan W.Immune checkpoint inhibitor therapy in solid organ transplant recipients: a patient-centered systematic review.J Am Acad Dermatol2020;82:1490-500

[71] Hu B,Sang XT.Liver graft rejection following immune checkpoint inhibitors treatment: a review.Med Oncol2019;36:94