Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. This malignancy is associated with poor prognosis and high mortality. Novel approaches for prolonging the overall survival of patients with advanced HCC are urgently needed. The antitumor activities of adoptive cell transfer therapy (ACT), such as strategies based on tumor-infiltrating lymphocytes and cytokine-induced killer cells, are more effective than those of traditional strategies. Currently, chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved numerous breakthroughs in the treatment of hematological malignancies, including relapsed or refractory lymphoblastic leukemia and refractory large B-cell lymphoma. Nevertheless, this approach only provides a modest benefit in the treatment of solid tumors. The clinical results of CAR-T immunotherapy for HCC that could be obtained at present are limited. Some published studies have demonstrated that CAR-T could inhibit tumor growth and cause severe side effects. In this review, we summarized the current application of ACT, the challenges encountered by CAR-T technology in HCC treatment, and some possible strategies for the future direction of immunotherapeutic research.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68(1): 7–30
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2): 115–132
Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018; 391(10127): 1301–1314
Makarova-Rusher OV, Medina-Echeverz J, Duffy AG, Greten TF. The yin and yang of evasion and immune activation in HCC. J Hepatol 2015; 62(6): 1420–1429
Greten TF, Wang XW, Korangy F. Current concepts of immune based treatments for patients with HCC: from basic science to novel treatment approaches. Gut 2015; 64(5): 842–848
Désert R, Rohart F, Canal F, Sicard M, Desille M, Renaud S, Turlin B, Bellaud P, Perret C, Clément B, Lê Cao KA, Musso O. Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection. Hepatology 2017; 66(5): 1502–1518
Galun D, Srdic-Rajic T, Bogdanovic A, Loncar Z, Zuvela M. Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies. J Hepatocell Carcinoma 2017; 4: 93–103
Chen C, Li K, Jiang H, Song F, Gao H, Pan X, Shi B, Bi Y,Wang H, Wang H, Li Z. Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma. Cancer Immunol Immunother 2017; 66(4): 475–489
Gao H, Li K, Tu H, Pan X, Jiang H, Shi B, Kong J,Wang H, Yang S, Gu J, Li Z. Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res 2014; 20 (24): 6418–6428
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378–390
Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391(10126): 1163–1173
Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebocontrolled, phase 3 trial. Lancet 2017; 389(10064): 56–66
Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol 2018; 15(10): 599–616
Bian H, Zheng JS, Nan G, Li R, Chen C, Hu CX, Zhang Y, Sun B, Wang XL, Cui SC, Wu J, Xu J, Wei D, Zhang X, Liu H, Yang W, Ding Y, Li J, Chen ZN. Randomized trial of [131I] metuximab in treatment of hepatocellular carcinoma after percutaneous radiofrequency ablation. J Natl Cancer Inst 2014; 106(9): dju239
Bogdanos DP, Gao B, Gershwin ME. Liver immunology. Compr Physiol 2013; 3(2): 567–598
Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol 2018; 19(3): 222–232
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, noncomparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389(10088): 2492–2502
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018; 19(7): 940–952
Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Seipp CA, Simpson C, Reichert CM. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985; 313(23): 1485–1492
Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA, Simpson C, Carter C, Bock S, Schwartzentruber D, Wei JP, White DE. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 1988; 319(25): 1676–1680
Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348(6230): 62–68
Wong YNS, Joshi K, Pule M, Peggs KS, Swanton C, Quezada SA, Linch M. Evolving adoptive cellular therapies in urological malignancies. Lancet Oncol 2017; 18(6): e341–e353
Jiang SS, Tang Y, Zhang YJ, Weng DS, Zhou ZG, Pan K, Pan QZ, Wang QJ, Liu Q, He J, Zhao JJ, Li J, Chen MS, Chang AE, Li Q, Xia JC. A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma. Oncotarget 2015; 6(38): 41339–41349
Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356(9232): 802–807
Yu X, Zhao H, Liu L, Cao S, Ren B, Zhang N, An X, Yu J, Li H, Ren X. A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol 2014; 34(2): 194–203
Hui D, Qiang L, Jian W, Ti Z, Da-Lu K. A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis 2009; 41(1): 36–41
Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, Gwak GY, Kim KM, Kim YJ, Lee JW, Yoon JH. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 2015; 148(7): 1383–1391.e6
Weng DS, Zhou J, Zhou QM, Zhao M, Wang QJ, Huang LX, Li YQ, Chen SP, Wu PH, Xia JC. Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas. J Immunother 2008; 31(1): 63–71
Pan CC, Huang ZL, Li W, Zhao M, Zhou QM, Xia JC, Wu PH. Serum α-fetoprotein measurement in predicting clinical outcome related to autologous cytokine-induced killer cells in patients with hepatocellular carcinoma undergone minimally invasive therapy. Chin J Cancer 2010; 29(6): 596–602
Hao MZ, Lin HL, Chen Q, Ye YB, Chen QZ, Chen MS. Efficacy of transcatheter arterial chemoembolization combined with cytokineinduced killer cell therapy on hepatocellular carcinoma: a comparative study. Chin J Cancer 2010; 29(2): 172–177
Maus MV, Fraietta JA, Levine BL, Kalos M, Zhao Y, June CH. Adoptive immunotherapy for cancer or viruses. Annu Rev Immunol 2014; 32(1): 189–225
Gross G, Eshhar Z. Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: counteracting off-tumor toxicities for safe CAR T cell therapy. Annu Rev Pharmacol Toxicol 2016; 56(1): 59–83
Jochems C, Schlom J. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood) 2011; 236(5): 567–579
Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 1998; 27(2): 407–414
Ma W, Wu L, Zhou F, Hong Z, Yuan Y, Liu Z. T cell-associated immunotherapy for hepatocellular carcinoma. Cell Physiol Biochem 2017; 41(2): 609–622
Mata-Molanes JJ, Sureda González M, Valenzuela Jiménez B, Martínez Navarro EM, Brugarolas Masllorens A. Cancer immunotherapy with cytokine-induced killer cells. Target Oncol 2017; 12 (3): 289–299
Morisaki T, Hirano T, Koya N, Kiyota A, Tanaka H, Umebayashi M, Onishi H, Katano M. NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors. Anticancer Res 2014; 34(8): 4529–4538
Pan K, Li YQ, Wang W, Xu L, Zhang YJ, Zheng HX, Zhao JJ, Qiu HJ, Weng DS, Li JJ, Wang QJ, Huang LX, He J, Chen SP, Ke ML, Wu PH, Chen MS, Li SP, Xia JC, Zeng YX. The efficacy of cytokine-induced killer cell infusion as an adjuvant therapy for postoperative hepatocellular carcinoma patients. Ann Surg Oncol 2013; 20(13): 4305–4311
Schmeel LC, Schmeel FC, Coch C, Schmidt-Wolf IG. Cytokineinduced killer (CIK) cells in cancer immunotherapy: report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 2015; 141(5): 839–849
Pan QZ,Wang QJ, Dan JQ, Pan K, Li YQ, Zhang YJ, Zhao JJ,Weng DS, Tang Y, Huang LX, He J, Chen SP, Ke ML, Chen MS, Wicha MS, Chang AE, Zeng YX, Li Q, Xia JC. A nomogram for predicting the benefit of adjuvant cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma. Sci Rep 2015; 5(1): 9202
Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol 2018; 15(1): 31–46
June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018; 359 (6382): 1361–1365
Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 2015; 385(9967): 517–528
Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med 2017; 9(9): 1183–1197
Liu Y, Chen X, Han W, Zhang Y. Tisagenlecleucel, an approved anti-CD19 chimeric antigen receptor T-cell therapy for the treatment of leukemia. Drugs Today (Barc) 2017; 53(11): 597–608
Vormittag P, Gunn R, Ghorashian S, Veraitch FS. A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol 2018; 53: 164–181
Di S, Li Z. Treatment of solid tumors with chimeric antigen receptor-engineered T cells: current status and future prospects. Sci China Life Sci 2016; 59(4): 360–369
Mount CW, Majzner RG, Sundaresh S, Arnold EP, Kadapakkam M, Haile S, Labanieh L, Hulleman E, Woo PJ, Rietberg SP, Vogel H, Monje M, Mackall CL. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nat Med 2018; 24 (5): 572–579
Fesnak AD, June CH, Levine BL. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer 2016; 16 (9): 566–581
Zhang BL, Qin DY, Mo ZM, Li Y, Wei W, Wang YS, Wang W, Wei YQ. Hurdles of CAR-T cell-based cancer immunotherapy directed against solid tumors. Sci China Life Sci 2016; 59(4): 340–348
Jiang Z, Jiang X, Chen S, Lai Y,Wei X, Li B, Lin S,Wang S,Wu Q, Liang Q, Liu Q, Peng M, Yu F, Weng J, Du X, Pei D, Liu P, Yao Y, Xue P, Li P. Anti-GPC3-CAR T cells suppress the growth of tumor cells in patient-derived xenografts of hepatocellular carcinoma. Front Immunol 2017; 7: 690
Saied A, Licata L, Burga RA, Thorn M, McCormack E, Stainken BF, Assanah EO, Khare PD, Davies R, Espat NJ, Junghans RP, Katz SC. Neutrophil: lymphocyte ratios and serum cytokine changes after hepatic artery chimeric antigen receptor-modified T-cell infusions for liver metastases. Cancer Gene Ther 2014; 21(11): 457–462
Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010; 18(4): 843–851
Burga RA, Thorn M, Point GR, Guha P, Nguyen CT, Licata LA, DeMatteo RP, Ayala A, Joseph Espat N, Junghans RP, Katz SC. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother 2015; 64(7): 817–829
Lim WA, June CH. The principles of engineering immune cells to treat cancer. Cell 2017; 168(4): 724–740
Adachi K, Kano Y, Nagai T, Okuyama N, Sakoda Y, Tamada K. IL- 7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol 2018; 36(4): 346–351
Milner JJ, Toma C, Yu B, Zhang K, Omilusik K, Phan AT, Wang D, Getzler AJ, Nguyen T, Crotty S, Wang W, Pipkin ME, Goldrath AW. Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours. Nature 2017; 552(7684): 253–257
Fako V, Wang XW. The status of transarterial chemoembolization treatment in the era of precision oncology. Hepat Oncol 2017; 4(2): 55–63
Unitt E, Marshall A, Gelson W, Rushbrook SM, Davies S, Vowler SL, Morris LS, Coleman N, Alexander GJ. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol 2006; 45(2): 246–253
Yoong KF, McNab G, Hübscher SG, Adams DH. Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. J Immunol 1998; 160(8): 3978–3988
Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, Schemmer P, Bruns H, Eiermann T, Price DA, Blum HE, Neumann- Haefelin C, Thimme R. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 2014; 59(4): 1415–1426
Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2015; 12(12): 681–700
Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science 2015; 348(6230): 74–80
Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, Pedroza-Gonzalez A, Polak WG, de Jonge J, Gaspersz M, Dong H, Thielemans K, Pan Q, JNM IJ, Bruno MJ, Kwekkeboom J. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology 2017; 153(4): 1107–1119.e10
Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR Tcells resistant to PD1 inhibition. Clin Cancer Res 2017; 23(9): 2255–2266
Neelapu SS, Tummala S, Kebriaei P,Wierda W, Gutierrez C, Locke FL, Komanduri KV, Lin Y, Jain N, Daver N, Westin J, Gulbis AM, Loghin ME, de Groot JF, Adkins S, Davis SE, Rezvani K, Hwu P, Shpall EJ. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat Rev Clin Oncol 2018; 15(1): 47–62
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (Nos. 31571434, 81874155, and 81872482) and the National Science and Technology Major Project (No. 2015CB553701).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://doi.org/creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the appropriate credit is given to the original author(s) and the source, and a link is provided to the Creative Commons license, indicating if changes were made.
About this article
Cite this article
Zhang, R., Zhang, Z., Liu, Z. et al. Adoptive cell transfer therapy for hepatocellular carcinoma. Front. Med. 13, 3–11 (2019). https://doi.org/10.1007/s11684-019-0684-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11684-019-0684-x