Recent updates on chimeric antigen receptor t cell therapy for hepatocellular carcinoma

ABSTRACT Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables T cells to specifically recognize tumor-associated antigens through genetic engineering

technology, thus exerting antitumor effects, and it has achieved encouraging outcomes in leukemia and lymphoma. Building on excellent progress, CAR-T therapy is also expected to work well in

solid tumors. Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed at an advanced stage. Current management options for HCC remain limited, and

although previous studies have indicated the feasibility of CAR-T cells, ideal therapeutic effects have not yet been achieved. This is, in part, due to the heterogeneity of tumor antigens,

high intratumor pressure, immunosuppressive microenvironment, CAR-T cell exhaustion, and serious adverse reactions, which compromise the therapeutic efficiency of CAR-T immunotherapy in HCC.

To overcoming these challenges, many ongoing preclinical and clinical studies were conducted. This review summarizes current CAR-T therapy targets in the treatment of HCC, discusses current

obstacles and possible solutions in the process, and describes potential strategies to improve the efficacy of CAR-T cells for patients with HCC. Access through your institution Buy or

subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online

access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which

are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS

CAR-T CELL THERAPY: CURRENT LIMITATIONS AND POTENTIAL STRATEGIES Article Open access 06 April 2021 EFFICACY OF ANTI-CD147 CHIMERIC ANTIGEN RECEPTORS TARGETING HEPATOCELLULAR CARCINOMA

Article Open access 23 September 2020 A NOVEL ENGINEERED IL-21 RECEPTOR ARMS T-CELL RECEPTOR-ENGINEERED T CELLS (TCR-T CELLS) AGAINST HEPATOCELLULAR CARCINOMA Article Open access 20 April

2024 REFERENCES * Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in

185 countries. CA Cancer J Clin. 2018;68:394–424. Article  PubMed  Google Scholar  * Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14. Article  PubMed  Google

Scholar  * Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30. Article  PubMed  Google Scholar  * Yu JX, Hubbard-Lucey VM, Tang J. The global pipeline of

cell therapies for cancer. Nat Rev Drug Discov. 2019;18:821–2. Article  CAS  Google Scholar  * Efficace F, Vignetti M. Quality of life and CAR-T cell therapy in children, adolescents, and

young adults with haematological malignancies. Lancet Oncol. 2019;20:1625–6. Article  PubMed  Google Scholar  * O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette

JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med.

2017;9:a984. Article  Google Scholar  * Yu JY, Wu XW, Yan JY, Yu H, Xu LW, Chi ZH, et al. Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma

patients. J Hematol Oncol. 2018;11:1. Article  PubMed  PubMed Central  Google Scholar  * Zheng ZQ, Tang Q, Feng ZQ. CAR-T cell therapy and its application in clinical cancer treatment.

Asia-Pac J Blood Types Genes. 2017;1:1–6. Google Scholar  * Sun B, Yang D, Dai HJ, Liu XY, Jia R, Cui XY, et al. Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells. Cancer

Immunol Res. 2019;7:1813–23. Article  CAS  PubMed  Google Scholar  * Xu YR, Zhou Y, Tang Q, Liu ZY, Huang XC, Yang TT, et al. Construction of Trop-2-targeted chimeric antigen

receptor-modified T cells and their effects on the proliferation of ovarian cancer cells in vitro. Acta Universitatis Medicinalis Nanjing. 2017;37:653–8. Google Scholar  * Nakatsura T,

Yoshitake Y, Senju S, Monji M, Komori H, Motomura Y, et al. Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. Biochem Biophys Res Commun.

2003;306:16–25. Article  CAS  PubMed  Google Scholar  * Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, et al. Glypican-3: a novel serum and histochemical marker for

hepatocellular carcinoma. Gastroenterology. 2003;125:89–97. Article  CAS  PubMed  Google Scholar  * Zhou FB, Shang WT, Yu XL, Tian J. Glypican-3: a promising biomarker for hepatocellular

carcinoma diagnosis and treatment. Med Res Rev. 2018;38:741–67. Article  CAS  PubMed  Google Scholar  * Stadlmann S, Gueth U, Baumhoer D, Moch H, Terracciano L, Singer G. Glypican-3

expression in primary and recurrent ovarian carcinomas. Int J Gynecol Pathol. 2007;26:341–4. Article  PubMed  Google Scholar  * Aviel-Ronen S, Lau SK, Pintilie M, Lau D, Liu N, Tsao MS, et

al. Glypican-3 is overexpressed in lung squamous cell carcinoma, but not in adenocarcinoma. Mod Pathol. 2008;21:817–25. Article  CAS  PubMed  Google Scholar  * Kandil D, Leiman G, Allegretta

M, Evans M. Glypican-3 protein expression in primary and metastatic melanoma: a combined immunohistochemistry and immunocytochemistry study. Cancer 2009;117:271–8. CAS  PubMed  Google

Scholar  * Montalbano M, Rastellini C, McGuire JT, Prajapati J, Shirafkan A, Vento R, et al. Role of Glypican-3 in the growth, migration and invasion of primary hepatocytes isolated from

patients with hepatocellular carcinoma. Cell Oncol. 2018;41:169–84. Article  CAS  Google Scholar  * Gao HP, Li K, Tu H, Pan XR, Jiang H, Shi BZ, et al. Development of T cells redirected to

glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res. 2014;20:6418–28. Article  CAS  PubMed  Google Scholar  * Jiang ZW, Jiang XF, Chen SM, Lai YX, Wei XR, Li BH, et al.

Anti-GPC3-CAR T cells suppress the growth of tumor cells in patient-derived xenografts of hepatocellular carcinoma. Front Immunol. 2016;7:690. PubMed  Google Scholar  * Gillespie JR,

Uversky VN. Structure and function of α-fetoprotein: a biophysical overview. Biochim Biophys Acta. 2000;1480:41–56. Article  CAS  PubMed  Google Scholar  * Liu H, Xu YY, Xiang JY, Long L,

Green S, Yang ZY, et al. Targeting alpha-fetoprotein (AFP)–MHC complex with CAR T-cell therapy for liver cancer. Clin Cancer Res. 2017;23:478–88. Article  CAS  PubMed  Google Scholar  *

Migliore C, Giordano S. Molecular cancer therapy: can our expectation be MET? Eur J Cancer. 2008;44:641–51. Article  CAS  PubMed  Google Scholar  * Eder JP, Vande Woude GF, Boerner SA,

LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009;15:2207–14. Article  CAS  PubMed  Google Scholar  * Huh CG, Factor VM, Sanchez A,

Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci USA. 2004;101:4477–82.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Borowiak M, Garratt AN, Wustefeld T, Strehle M, Trautwein C, Birchmeier C. Met provides essential signals for liver regeneration. Proc

Natl Acad Sci USA. 2004;101:10608–13. Article  CAS  PubMed  PubMed Central  Google Scholar  * Qi XS, Guo XZ, Han GH, Li HY, Chen J. MET inhibitors for treatment of advanced hepatocellular

carcinoma: a review. World J Gastroenterol. 2015;21:5445–53. Article  CAS  PubMed  PubMed Central  Google Scholar  * Huang XC. Fabrication of c-Met Chimeric antigen receptor T cells and

killing of hepatocellular carcinoma cells in vitro and in vivo. Nanjing Medical University; 2018. * Li T, Jiang W, Gu X, Li B, Wang JJ, Shi X, et al. Optimization, construction and

biological characterization of novel bispecific c-Met/PD-L1 scFv-Fc fusion protein. Acta Universitatis Medicinalis Nanjing. 2019;39:1415–20. Google Scholar  * Kufe DW. Mucins in cancer:

function, prognosis and therapy. Nat Rev Cancer. 2009;9:874–85. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang J, Liu GM, Li QS, Wang F, Xie F, Zhai RP, et al. Mucin1 promotes

the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions. Oncotarget. 2015;6:19264–78. Article  PubMed 

PubMed Central  Google Scholar  * Ma YD, Wang Z, Gong RZ, Li LF, Wu HP, Jin HJ, et al. Specific cytotoxicity of MUC1 chimeric antigen receptor-engineered Jurkat T cells against

hepatocellular carcinoma. Academic J Second Mil Med Univ. 2014;35:1177–82. Article  Google Scholar  * Terris B, Cavard C, Perret C. EpCAM, a new marker for cancer stem cells in

hepatocellular carcinoma. J Hepatol. 2010;52:280–1. Article  CAS  PubMed  Google Scholar  * Yamashita T, Forgues M, Wang W, Kim JW, Ye QH, Jia HL, et al. EpCAM and alpha-fetoprotein

expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008;68:1451–61. Article  CAS  PubMed  Google Scholar  * Zhang BL, Li D, Gong YL, Huang Y, Qin DY, Jiang

L, et al. Preclinical evaluation of chimeric antigen receptor-modified T cells specific to epithelial cell adhesion molecule for treating colorectal cancer. Hum Gene Ther. 2019;30:402–12.

Article  CAS  PubMed  Google Scholar  * Ferrandina G, Petrillo M, Bonanno G, Scambia G. Targeting CD133 antigen in cancer. Expert Opin Ther Targets. 2009;13:823–37. Article  CAS  PubMed 

Google Scholar  * Kohga K, Tatsumi T, Takehara T, Tsunematsu H, Shimizu S, Yamamoto M, et al. Expression of CD133 confers malignant potential by regulating metalloproteinases in human

hepatocellular carcinoma. J Hepatol. 2010;52:872–9. Article  CAS  PubMed  Google Scholar  * Song W, Li H, Tao K, Li R, Song Z, Zhao Q, et al. Expression and clinical significance of the stem

cell marker CD133 in hepatocellular carcinoma. Int J Clin Pract. 2008;62:1212–8. Article  CAS  PubMed  Google Scholar  * Wang Y, Chen MX, Wu ZQ, Tong C, Dai HR, Guo YL, et al.

CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. Oncoimmunology. 2018;7:e1440169. Article  PubMed  PubMed Central  Google Scholar  * Li Y, Xu J, Chen L,

Zhong WD, Zhang Z, Mi L, et al. HAb18G (CD147), a cancer-associated biomarker and its role in cancer detection. Histopathology. 2009;54:677–87. Article  CAS  PubMed  Google Scholar  * Sun

JX, Hemler ME. Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions. Cancer Res. 2001;61:2276. CAS  PubMed  Google Scholar  *

Zhu SJ, Li YH, Zhang Y, Wang XX, Gong L, Han XJ, et al. Expression and clinical implications of HAb18G/CD147 in hepatocellular carcinoma. Hepatol Res. 2015;45:97–106. Article  CAS  PubMed 

Google Scholar  * Fan WZ, Wu YQ, Lu MJ, Yao W, Cui W, Zhao Y, et al. A meta-analysis of the efficacy and safety of iodine [131I] metuximab infusion combined with TACE for treatment of

hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 2019;43:451–9. Article  CAS  PubMed  Google Scholar  * Bian HJ, Zheng JS, Nan G, Li R, Chen CS, Hu CX, et al. Randomized trial of

[131I] metuximab in treatment of hepatocellular carcinoma after percutaneous radiofrequency ablation. J Natl Cancer Inst. 2014;106:dju239. Article  PubMed  Google Scholar  * Chen ZN, Mi L,

Xu J, Song F, Zhang Q, Zhang Z, et al. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical Phase I/II trials. Int J Radiat Oncol Biol

Phys. 2006;65:435–44. Article  CAS  PubMed  Google Scholar  * Zhang RY, Wei D, Liu ZK, Yong YL, Wei W, Zhang ZY, et al. Doxycycline inducible chimeric antigen receptor T cells targeting

CD147 for hepatocellular carcinoma therapy. Front Cell Dev Biol. 2019;7:233. Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhang JY, Basher F, Wu JD. NKG2D ligands in tumor

immunity: two sides of a coin. Front Immunol. 2015;6:97. Article  CAS  PubMed  PubMed Central  Google Scholar  * Jinushi M, Takehara T, Tatsumi T, Kanto T, Groh V, Spies T, et al. Expression

and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer. 2003;104:354–61. Article  CAS  PubMed  Google Scholar  * Fang L, Gong JY,

Wang Y, Liu RG, Li ZS, Wang Z, et al. MICA/B expression is inhibited by unfolded protein response and associated with poor prognosis in human hepatocellular carcinoma. J Exp Clin Cancer Res.

2014;33:76. Article  PubMed  PubMed Central  Google Scholar  * Kamimura H, Yamagiwa S, Tsuchiya A, Takamura M, Matsuda Y, Ohkoshi S, et al. Reduced NKG2D ligand expression in hepatocellular

carcinoma correlates with early recurrence. J Hepatol. 2011;56:381–8. Article  PubMed  Google Scholar  * Sun B, Yang D, Dai HJ, Liu XY, Jia R, Cui XY, et al. Eradication of hepatocellular

carcinoma by NKG2D-based CAR-T cells. Cancer Immunol Res. 2019;7:1813–23. Article  CAS  PubMed  Google Scholar  * Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis

and management of hepatocellular carcinoma. Clin Liver Dis. 2001;5:145. Article  CAS  PubMed  Google Scholar  * Li T, Jiang W, Ji GZ, Feng ZQ. The research advances of CAR-T cell therapy in

solid tumor. J Med Postgr.a 2019;32:886–90. Google Scholar  * Zhao W, Jia LZ, Zhang MJ, Huang XC, Qian P, Tang Q, et al. The killing effect of novel bi-specific Trop2/PD-L1 CAR-T cell

targeted gastric cancer. Am J Cancer Res. 2019;9:1846. CAS  PubMed  PubMed Central  Google Scholar  * Chen C, Li KS, Jiang H, Song F, Gao HP, Pan XR, et al. 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;66:475–89.

Article  CAS  PubMed  Google Scholar  * Liu XJ, Jiang SG, Fang CY, Yang SY, Olalere D, Pequignot EC, et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an

increased therapeutic index against tumors in mice. Cancer Res. 2015;75:3596–607. Article  CAS  PubMed  PubMed Central  Google Scholar  * Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S,

Olivares S, et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 2015;75:3505–18. Article  CAS 

PubMed  PubMed Central  Google Scholar  * Feng ZQ. Reconsidering CAR-T cell therapy for solid tumors. J Med Postgra. 2019;32:337–40. Google Scholar  * Caruana I, Savoldo B, Hoyos V, Weber G,

Liu H, Kim ES, et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 2015;21:524–9. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Kakarla S, Chow KK, Mata M, Shaffer DR, Song XT, Wu MF, et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther. 2013;21:1611–20.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Burga RA, Thorn M, Point GR, Guha P, Nguyen CT, Licata LA, et al. 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;64:817–29. Article  CAS  PubMed  PubMed Central  Google Scholar  * Katz SC, Burga

RA, McCormack E, Wang LJ, Mooring W, Point GR, et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver

metastases. Clin Cancer Res. 2015;21:3149–59. Article  CAS  PubMed  PubMed Central  Google Scholar  * Do HTT, Lee CH, Cho J. Chemokines and their receptors: multifaceted roles in cancer

progression and potential value as cancer prognostic markers. Cancers. 2020;12:287. Article  CAS  PubMed Central  Google Scholar  * Nagarsheth N, Wicha MS, Zou WP. Chemokines in the cancer

microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017;17:559–72. Article  CAS  PubMed  PubMed Central  Google Scholar  * Liu GN, Rui W, Zheng HL, Huang DS, Yu

F, Zhang YW, et al. CXCR2-modified CAR-T cells have enhanced trafficking ability that improves treatment of hepatocellular carcinoma. Eur J Immunol. 2020;50:712–24. Article  CAS  PubMed 

Google Scholar  * Gu X, Tang Q. Tumor immune microenvironment: sanctuary of tumor and target for immunotherapy. Asia-Pac J Blood Types Genes. 2018;2:141–8. Google Scholar  * Ligtenberg MA,

Mougiakakos D, Mukhopadhyay M, Witt K, Lladser A, Chmielewski M, et al. Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative

stress-induced loss of antitumor activity. J Immunol. 2016;196:759–66. Article  CAS  PubMed  Google Scholar  * Newick K, O’Brien S, Sun J, Kapoor V, Maceyko S, Lo A, et al. Augmentation of

CAR T-cell trafficking and antitumor efficacy by blocking protein kinase A localization. Cancer Immunol Res. 2016;4:541–51. Article  CAS  PubMed  PubMed Central  Google Scholar  * Hou AJ,

Chang ZL, Lorenzini MH, Zah E, Chen YY. TGF-β-responsive CAR-T cells promote anti-tumor immune function. Bioeng Transl Med. 2018;3:75–86. Article  CAS  PubMed  PubMed Central  Google Scholar

  * Spear P, Barber A, Rynda-Apple A, Sentman CL. Chimeric antigen receptor T cells shape myeloid cell function within the tumor microenvironment through IFN-γ and GM-CSF. J Immunol.

2012;188:6389–98. Article  CAS  PubMed  Google Scholar  * Webb ES, Liu P, Baleeiro R, Lemoine NR, Yuan M, Wang YH. Immune checkpoint inhibitors in cancer therapy. J Biomed Res.

2018;32:317–26. PubMed  Google Scholar  * Guo XL, Jiang H, Shi BZ, Zhou M, Zhang HH, Shi ZM, et al. Disruption of PD-1 enhanced the anti-tumor activity of chimeric antigen receptor T cells

against hepatocellular carcinoma. Front Pharmacol. 2018;9:1118. Article  CAS  PubMed  PubMed Central  Google Scholar  * Pan ZY, Di SM, Shi BZ, Jiang H, Shi ZM, Liu Y, et al. Increased

antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1–CH3 fusion protein. Cancer Immunol Immunother. 2018;67:1621–34.

Article  CAS  PubMed  Google Scholar  * Sasse A, Carmo R. Sorafenib for advanced hepatocellular carcinoma (HCC) in the public health setting in Brazil: a cost-effectiveness analysis. Ann

Oncol. 2019;30 Suppl 4:v66. Article  Google Scholar  * Wu XQ, Luo H, Shi BZ, Di SM, Sun RX, Su JW, et al. Combined antitumor effects of sorafenib and GPC3-CAR T cells in mouse models of

hepatocellular carcinoma. Mol Ther. 2019;27:1483–94. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang XL, Walter M, Urak R, Weng LH, Huynh C, Lim L, et al. Lenalidomide enhances

the function of CS1 chimeric antigen receptor–redirected T cells against multiple myeloma. Clin Cancer Res. 2018;24:106–19. Article  CAS  PubMed  Google Scholar  * Wherry EJ. T cell

exhaustion. Nat Immunol. 2011;12:492–9. Article  CAS  PubMed  Google Scholar  * Markley JC, Sadelain M. IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell–mediated

rejection of systemic lymphoma in immunodeficient mice. Blood. 2010;115:3508–19. Article  CAS  PubMed  PubMed Central  Google Scholar  * Liu Y, Di SM, Shi BZ, Zhang HH, Wang Y, Wu XQ, et al.

Armored inducible expression of IL-12 enhances antitumor activity of glypican-3-targeted chimeric antigen receptor-engineered T cells in hepatocellular carcinoma. J Immunol.

2019;203:198–207. Article  CAS  PubMed  Google Scholar  * Batra SA, Purva R, Linjie G, Amy NC, Julien F, Julien B, et al. Glypican-3-specific CAR T cells co-expressing IL15 and IL21 have

superior expansion and antitumor activity against hepatocellular carcinoma. Cancer. Immunol Res. 2020;8:309–20. CAS  Google Scholar  * Chmielewski M, Abken H. CAR T cells releasing IL-18

convert to T-Bet high FoxO1 low effectors that exhibit augmented activity against advanced solid tumors. Cell Rep. 2017;21:3205–19. Article  CAS  PubMed  Google Scholar  * Ma XC, Shou PS,

Smith C, Chen YH, Du HW, Sun C, et al. Interleukin-23 engineering improves CAR T cell function in solid tumors. Nat Biotechnol. 2020;38:448–59. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Hu W, Huang X, Huang XY, Chen WW, Hao LD, Chen ZB. Chimeric antigen receptor modified T cell (CAR-T) co-expressed with ICOSL-41BB promote CAR-T proliferation and tumor rejection.

Biomed Pharmacother. 2019;118:109333. Article  CAS  PubMed  Google Scholar  * Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003;3:781–90. Article  CAS 

PubMed  Google Scholar  * Zhao RC, Cheng L, Jiang ZW, Wei XR, Li BH, Wu QT, et al. DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T

cells. Oncoimmunology. 2018;8:e1509173. Article  PubMed  PubMed Central  Google Scholar  * Siriwon N, Kim YJ, Siegler E, Chen XH, Rohrs JA, Liu YR, et al. CAR-T cells surface-engineered with

drug-encapsulated nanoparticles can ameliorate intratumoral T-cell hypofunction. Cancer Immunol Res. 2018;6:812–24. Article  CAS  PubMed  Google Scholar  * Chen Q, Hu QY, Dukhovlinova E,

Chen GJ, Ahn S, Wang C, et al. Photothermal therapy promotes tumor infiltration and antitumor activity of CAR T cells. Adv Mater. 2019;31:e1900192. Article  PubMed  PubMed Central  Google

Scholar  * Meng WCS, Pan YL, Zhao XX. Epirubicin-gold nanoparticles suppress hepatocellular carcinomaxenograft growth in nude mice. J Biomed Res 2015;29:486–90. PubMed Central  Google

Scholar  * Ma WJ, Zhu DM, Li JH, Chen X, Xie W, Jiang X, et al. Coating biomimetic nanoparticles with chimeric antigen receptor T cell-membrane provides high specificity for hepatocellular

carcinoma photothermal therapy treatment. Theranostics. 2020;10:1281–95. Article  PubMed  PubMed Central  Google Scholar  * Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera

J, et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia. 2010;24:1160–70. Article  CAS 

PubMed  PubMed Central  Google Scholar  * Wang XL, Chang WC, Wong CW, Colcher D, Sherman M, Ostberg JR, et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking,

and ablation of engineered cells. Blood. 2011;118:1255–63. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of

therapeutic T cells through a small molecule-gated chimeric receptor. Science. 2015;350:b4077. Article  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Zhenqing Feng and

Xinjian Liu (National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China) for their revision and reading of the manuscript. FUNDING This work

is supported by the National Natural Science Foundation of China (No. 81773268). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * National Health Commission Key Laboratory of Antibody

Techniques, Nanjing Medical University, Nanjing, 211166, China Jiaojiao Guo & Qi Tang * Department of Pathology, Nanjing Medical University, Nanjing, 211166, China Jiaojiao Guo & Qi

Tang Authors * Jiaojiao Guo View author publications You can also search for this author inPubMed Google Scholar * Qi Tang View author publications You can also search for this author

inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Qi Tang. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ADDITIONAL

INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Guo, J., Tang, Q. Recent updates on chimeric antigen receptor T cell therapy for hepatocellular carcinoma. _Cancer Gene Ther_ 28, 1075–1087

(2021). https://doi.org/10.1038/s41417-020-00259-4 Download citation * Received: 15 June 2020 * Revised: 04 November 2020 * Accepted: 04 November 2020 * Published: 26 January 2021 * Issue

Date: November 2021 * DOI: https://doi.org/10.1038/s41417-020-00259-4 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry,

a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative