Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review

Author(s): Jianguo Qiu, Wei Tang, Chengyou Du*

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 9 , 2020


  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Immune checkpoint modulators, such as the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitor have been investigated with encouraging results for hepatocellular carcinoma (HCC). However, the safety of this strategy in patients with previous liver transplantation (LT) is not well studied.

Objective: To explore the safety and feasibility of immune checkpoints inhibitors in recurrent and metastatic HCC patients on a background of LT.

Methods: A case of recurrent, refractory, metastatic HCC after LT, where PD-1 inhibitor was initiated, was described and related literature was reviewed.

Results: There was complete remission in lung metastases and the partial radiological response of metastatic retroperitoneal lymph node to the drug with no liver graft rejection after 13 cycles of PD- 1 inhibitor injection. PD-1inhibitor, at least in this patient, was verified to play an important role in controlling tumor progression and prolonging patient survival.

Conclusion: This novel drug might be a useful method to allow doctors to guarantee a better chance for long-term survival in recurrent, metastatic HCC patients with the previous LT. However, it should be used with caution in allograft recipients due to the risk of acute graft rejection, further larger, prospective studies are needed to determine optimal immunomodulatory therapy to achieve optimal anti-tumor efficacy with transplant liver preservation.

Keywords: Immune checkpoint inhibitors, hepatocellular carcinoma, liver transplantation, case report, graft rejection, optimal immunomodulatory therapy.

[1]
O’Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 2007; 110(12): 2614-27.
[http://dx.doi.org/10.1002/cncr.23086] [PMID: 18000991]
[2]
Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27(4): 450-61.
[http://dx.doi.org/10.1016/j.ccell.2015.03.001] [PMID: 25858804]
[3]
Brahmer JR, Pardoll DM. Immune checkpoint inhibitors: making immunotherapy a reality for the treatment of lung cancer. Cancer Immunol Res 2013; 1(2): 85-91.
[http://dx.doi.org/10.1158/2326-6066.CIR-13-0078] [PMID: 24777499]
[4]
Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2015; 12(12): 681-700.
[http://dx.doi.org/10.1038/nrgastro.2015.173] [PMID: 26484443]
[5]
Chen Y, Duda DG. Targeting immunosuppression after standard sorafenib treatment to facilitate immune checkpoint blockade in hepatocellular carcinoma - an auto-commentary on clinical potential and future development. OncoImmunology 2015; 4(10) e1029703
[http://dx.doi.org/10.1080/2162402X.2015.1029703]] [PMID: 26451297]
[6]
Friend BD, Venick RS, McDiarmid SV, et al. Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma. Pediatr Blood Cancer 2017; 64(12) e26682
[http://dx.doi.org/10.1002/pbc.26682]] [PMID: 28643391]
[7]
Varkaris A, Lewis DW, Nugent FW. Preserved liver transplant after PD-1 pathway inhibitor for hepatocellular carcinoma. Am J Gastroenterol 2017; 112(12): 1895-6.
[http://dx.doi.org/10.1038/ajg.2017.387] [PMID: 29215617]
[8]
Rammohan A, Reddy MS, Farouk M, Vargese J, Rela M. Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: The silver bullet? Hepatology 2018; 67(3): 1166-8.
[http://dx.doi.org/10.1002/hep.29575] [PMID: 29023959]
[9]
De Toni EN, Gerbes AL. Tapering of immunosuppression and sustained treatment with nivolumab in a liver transplant recipient. Gastroenterology 2017; 152(6): 1631-3.
[http://dx.doi.org/10.1053/j.gastro.2017.01.063] [PMID: 28384452]
[10]
DeLeon TT, Salomao MA, Aqel BA, et al. Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience. J Gastrointest Oncol 2018; 9(6): 1054-62.
[http://dx.doi.org/10.21037/jgo.2018.07.05] [PMID: 30603124]
[11]
Biondani P, De Martin E, Samuel D. Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient. Ann Oncol 2018; 29(1): 286-7.
[http://dx.doi.org/10.1093/annonc/mdx548] [PMID: 29293878]
[12]
Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology 2016; 150(4): 835-53.
[http://dx.doi.org/10.1053/j.gastro.2015.12.041] [PMID: 26795574]
[13]
Norsa’adah B, Nurhazalini-Zayani CG. Epidemiology and survival of hepatocellular carcinoma in north-east Peninsular Malaysia. Asian Pac J Cancer Prev 2013; 14(11): 6955-9.
[http://dx.doi.org/10.7314/APJCP.2013.14.11.6955] [PMID: 24377632]
[14]
Kane RC, Farrell AT, Madabushi R, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist 2009; 14(1): 95-100.
[http://dx.doi.org/10.1634/theoncologist.2008-0185] [PMID: 19144678]
[15]
Pinter M, Sieghart W, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist 2009; 14(1): 70-6.
[http://dx.doi.org/10.1634/theoncologist.2008-0191] [PMID: 19144684]
[16]
Berretta M, Di Benedetto F, Dal Maso L, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma in HIV-positive patients. Anticancer Drugs 2013; 24(2): 212-8.
[http://dx.doi.org/10.1097/CAD.0b013e32835c032f] [PMID: 23197082]
[17]
Bruix J, Tak WY, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer 2013; 49(16): 3412-9.
[http://dx.doi.org/10.1016/j.ejca.2013.05.028] [PMID: 23809766]
[18]
Bruix J, Qin S, Merle P, et al. RESORCE Investigators.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389(10064): 56-66.
[http://dx.doi.org/10.1016/S0140-6736(16)32453-9] [PMID: 27932229]
[19]
Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28(19): 3167-75.
[http://dx.doi.org/10.1200/JCO.2009.26.7609] [PMID: 20516446]
[20]
Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther 2015; 37(4): 764-82.
[http://dx.doi.org/10.1016/j.clinthera.2015.02.018] [PMID: 25823918]
[21]
Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015; 16(3): 257-65.
[http://dx.doi.org/10.1016/S1470-2045(15)70054-9] [PMID: 25704439]
[22]
Winograd R, Byrne KT, Evans RA, et al. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol Res 2015; 3(4): 399-411.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0215] [PMID: 25678581]
[23]
Hato T, Goyal L, Greten TF, Duda DG, Zhu AX. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology 2014; 60(5): 1776-82.
[http://dx.doi.org/10.1002/hep.27246] [PMID: 24912948]
[24]
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389(10088): 2492-502.
[http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID: 28434648]
[25]
Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015; 14(4): 847-56.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0983] [PMID: 25695955]
[26]
Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 2017; 18(1): 31-41.
[http://dx.doi.org/10.1016/S1470-2045(16)30624-6] [PMID: 27932067]
[27]
Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017; 377(25): 2500-1.
[http://dx.doi.org/10.1056/NEJMc1713444] [PMID: 29262275]
[28]
Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 2007; 19(7): 813-24.
[http://dx.doi.org/10.1093/intimm/dxm057] [PMID: 17606980]
[29]
Riella LV, Paterson AM, Sharpe AH, Chandraker A. Role of the PD-1 pathway in the immune response. Am J Transplant 2012; 12(10): 2575-87.
[http://dx.doi.org/10.1111/j.1600-6143.2012.04224.x] [PMID: 22900886]
[30]
Tanaka K, Albin MJ, Yuan X, et al. PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection. J Immunol 2007; 179(8): 5204-10.
[http://dx.doi.org/10.4049/jimmunol.179.8.5204] [PMID: 17911605]
[31]
Starke A, Lindenmeyer MT, Segerer S, et al. Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses. Kidney Int 2010; 78(1): 38-47.
[http://dx.doi.org/10.1038/ki.2010.97] [PMID: 20393451]
[32]
Lipson EJ, Bodell MA, Kraus ES, Sharfman WH. Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma. J Clin Oncol 2014; 32(19): e69-71.
[http://dx.doi.org/10.1200/JCO.2013.49.2314] [PMID: 24493726]
[33]
Herz S, Höfer T, Papapanagiotou M, et al. Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient. Eur J Cancer 2016; 67: 66-72.
[http://dx.doi.org/10.1016/j.ejca.2016.07.026] [PMID: 27614165]
[34]
Kittai AS, Oldham H, Cetnar J, Taylor M. Immune checkpoint inhibitors in organ transplant patients. J Immunother 2017; 40(7): 277-81.
[http://dx.doi.org/10.1097/CJI.0000000000000180] [PMID: 28719552]
[35]
Barnett R, Barta VS, Jhaveri KD. Preserved renal-allograft function and the PD-1 pathway inhibitor nivolumab. N Engl J Med 2017; 376(2): 191-2.
[http://dx.doi.org/10.1056/NEJMc1614298] [PMID: 28076715]
[36]
Spain L, Higgins R, Gopalakrishnan K, Turajlic S, Gore M, Larkin J. Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma. Ann Oncol 2016; 27(6): 1135-7.
[http://dx.doi.org/10.1093/annonc/mdw130] [PMID: 26951628]
[37]
Alhamad T, Venkatachalam K, Linette GP, Brennan DC. Checkpoint inhibitors in kidney transplant recipients and the potential risk of rejection. Am J Transplant 2016; 16(4): 1332-3.
[http://dx.doi.org/10.1111/ajt.13711] [PMID: 26752406]
[38]
Boils CL, Aljadir DN, Cantafio AW. Use of the PD-1 pathway inhibitor nivolumab in a renal transplant patient with malignancy. Am J Transplant 2016; 16(8): 2496-7.
[http://dx.doi.org/10.1111/ajt.13786] [PMID: 26988410]
[39]
Lipson EJ, Bagnasco SM, Moore J Jr, et al. Tumor regression and allograft rejection after administration of anti-PD-1. N Engl J Med 2016; 374(9): 896-8.
[http://dx.doi.org/10.1056/NEJMc1509268] [PMID: 26962927]
[40]
Ranganath HA, Panella TJ. Administration of ipilimumab to a liver transplant recipient with unresectable metastatic melanoma. J Immunother 2015; 38(5): 211.
[http://dx.doi.org/10.1097/CJI.0000000000000077] [PMID: 25962109]
[41]
Morales RE, Shoushtari AN, Walsh MM, Grewal P, Lipson EJ, Carvajal RD. Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation. J Immunother Cancer 2015; 3: 22.
[http://dx.doi.org/10.1186/s40425-015-0066-0] [PMID: 26082835]
[42]
Wu CK, Juang GD, Lai HC. Tumor regression and preservation of graft function after combination with anti-PD-1 immunotherapy without immunosuppressant titration. Ann Oncol 2017; 28(11): 2895-6.
[http://dx.doi.org/10.1093/annonc/mdx409] [PMID: 29045528]
[43]
Dueland S, Guren TK, Boberg KM, et al. Acute liver graft rejection after ipilimumab therapy. Ann Oncol 2017; 28(10): 2619-20.
[http://dx.doi.org/10.1093/annonc/mdx281] [PMID: 28961840]
[44]
Ong M, Ibrahim AM, Bourassa-Blanchette S, Canil C, Fairhead T, Knoll G. Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. J Immunother Cancer 2016; 4(1): 64.
[http://dx.doi.org/10.1186/s40425-016-0171-8] [PMID: 27777773]
[45]
Owonikoko TK, Kumar M, Yang S, et al. Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report. Cancer Immunol Immunother 2017; 66(1): 45-50.
[http://dx.doi.org/10.1007/s00262-016-1918-2] [PMID: 27771741]
[46]
Kuo JC, Lilly LB, Hogg D. Immune checkpoint inhibitor therapy in a liver transplant recipient with a rare subtype of melanoma: a case report and literature review. Melanoma Res 2018; 28(1): 61-4.
[http://dx.doi.org/10.1097/CMR.0000000000000410] [PMID: 29140833]
[47]
Jose A, Yiannoullou P, Bhutani S, et al. Renal allograft failure after ipilimumab therapy for metastatic melanoma: a case report and review of the literature[C]//Transplantation proceedings Elsevier 2016; 48((9)): 3137-41.
[48]
Qin R, Salama AKS. Report of ipilimumab in a heart transplant patient with metastatic melanoma on tacrolimus. Melanoma Manag 2015; 2(4): 311-4.
[http://dx.doi.org/10.2217/mmt.15.27] [PMID: 30190859]
[49]
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224(1): 166-82.
[http://dx.doi.org/10.1111/j.1600-065X.2008.00662.x] [PMID: 18759926]
[50]
Poirier N, Azimzadeh A M, Zhang T, et al. Inducing CTLA-4–dependent immune regulation by selective CD28 blockade promotesregulatory T cells in organ transplantation. Science translational medicine 2010; 2(17): 17ra10-0.
[51]
Schoop R, Wahl P, Le Hir M, et al. Suppressed T-cell activation by IFN-γ-induced expression of PD-L1 on renal tubular epithelial cells[J] 2015; 2(4): 311-4.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 9
Year: 2020
Page: [720 - 727]
Pages: 8
DOI: 10.2174/1568009620666200520084415
Price: $65

Article Metrics

PDF: 105
HTML: 4