23 June 2026: Review Articles
A Review of Recent Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapy for Hepatocellular Carcinoma
Xiaopan Lv ABE 1, Xuemei Chen BCE 1, Yuxin Ge AC 1, Guifei Si DF 1, Yuquan Li BCD 1, Xiuping Li DF 2, Xuemin Yuan ACFG 2*
DOI: 10.12659/MSM.953528
Med Sci Monit 2026; 32:e953528
Abstract
ABSTRACT: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and poses a major global health burden. It remains a leading cause of cancer-related death worldwide, with persistently high incidence and mortality in regions affected by chronic viral hepatitis, cirrhosis, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease. Although surgical resection, liver transplantation, locoregional therapies, molecular targeted agents, and immune checkpoint inhibitors have improved treatment options, outcomes for advanced HCC remain unsatisfactory. Chimeric antigen receptor (CAR) T-cell therapy is an adoptive cellular immunotherapy in which T lymphocytes are genetically engineered to recognize tumor-associated antigens and eliminate malignant cells. CAR-T-cell therapy has achieved major clinical success in hematologic malignancies, but its application in HCC is still developing because of tumor heterogeneity, antigen escape, limited T-cell trafficking, and an immunosuppressive tumor microenvironment. Recent studies have investigated several HCC-associated targets, including glypican-3 (GPC3), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), CD133, epidermal growth factor receptor variant III (EGFRvIII), B7 homolog 3 (B7H3), mucin 1 (MUC1), natural killer group 2 member D ligand (NKG2DL), programmed death-ligand 1 (PD-L1)/c-Met, CD147, CD44, and epithelial cell adhesion molecule (EpCAM). This article provides a target-oriented synthesis of HCC-related CAR-T-cell therapy, summarizes registered clinical studies according to antigen target, CAR design, trial phase, administration route, and available outcomes, and discusses how CAR structural evolution may influence therapeutic development in HCC. This article aims to review recent advances in CAR-T-cell therapy for hepatocellular carcinoma.
Keywords: Carcinoma, Hepatocellular, Receptors, Chimeric Antigen, T-Lymphocytes, Immunotherapy, Adoptive, review
Introduction
Hepatocellular carcinoma (HCC) is the predominant histologic subtype of primary liver cancer and represents a substantial global health burden [1–4]. Liver cancer remains among the leading causes of cancer-related death worldwide, and HCC accounts for most primary liver cancer cases [3–6]. The incidence and mortality of HCC remain high in regions with prevalent chronic hepatitis virus infection, cirrhosis, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease [4,7,8].
Curative-intent treatments for early-stage HCC include surgical resection, local ablation, and liver transplantation [9–11]. However, many patients are diagnosed at an advanced stage or have underlying chronic liver disease that limits curative treatment options [4,7,8,12]. Systemic treatment has evolved from sorafenib to several targeted agents and immune checkpoint inhibitor-based strategies, including regorafenib, lenvatinib, cabozantinib, ramucirumab, pembrolizumab, and nivolumab [13–25]. Despite these advances, durable responses remain limited in many patients with advanced HCC, supporting the need for new therapeutic approaches [20,23–25].
Chimeric antigen receptor (CAR) T-cell therapy is a form of adoptive cellular immunotherapy in which T cells are genetically modified to express synthetic receptors that recognize tumor-associated antigens independently of major histocompatibility complex (MHC) presentation [26,27]. CAR-T-cell therapy has produced substantial clinical responses in several hematologic malignancies, establishing a strong rationale for its exploration in solid tumors [28–31]. However, the translation of CAR-T-cell therapy into solid tumors has been constrained by antigen heterogeneity, inadequate T-cell trafficking and infiltration, physical stromal barriers, and immunosuppressive signals within the tumor microenvironment (TME) [32–35].
Several recent reviews have summarized CAR-T-cell therapy for HCC from broad translational and mechanistic perspectives [36,37]. Compared with these reviews, this article aims to review recent advances in CAR-T-cell therapy for hepatocellular carcinoma.
CAR-T Immunotherapy
CAR-T-cell therapy uses genetically modified T lymphocytes to recognize tumor-associated antigens and mediate tumor cell killing [26,27]. Peripheral blood mononuclear cells (PBMCs) are commonly obtained through leukapheresis, followed by T-cell enrichment, activation, genetic transduction or transfection, ex vivo expansion, quality control, and reinfusion into the patient [26,27,38,39]. The single-chain variable fragment (scFv) within the extracellular domain mediates antigen recognition, whereas intracellular signaling domains activate T-cell cytotoxicity, proliferation, and cytokine release [27,40,41]. Figure 1 illustrates the generation process, target recognition, and antitumor mechanisms of chimeric antigen receptor T-cell therapy in hepatocellular carcinoma (Figure 1).
Unlike conventional T-cell receptor (TCR)-mediated recognition, CAR-mediated antigen recognition does not require peptide presentation by MHC molecules [27]. This feature allows CAR-T cells to recognize surface antigens on tumor cells even when tumors downregulate MHC expression as an immune-evasion mechanism [27,42]. Nevertheless, the efficacy of CAR-T-cell therapy in solid tumors depends on target antigen specificity, antigen density, T-cell persistence, and the suppressive characteristics of the TME [32–35].
Structural Design and Evolution of CAR-T Cells
A CAR molecule generally contains an extracellular antigen-binding domain, a hinge or spacer region, a transmembrane domain, and intracellular signaling modules [40,41]. The extracellular antigen-binding domain is most commonly derived from an antibody scFv and determines target specificity [27,40]. The hinge and transmembrane domains affect receptor flexibility, stability, antigen accessibility, and cell-surface expression [40].
First-generation CARs contained CD3ζ or Fc receptor gamma chain signaling domains but lacked costimulatory domains, resulting in limited in vivo persistence and antitumor activity [41,43,44]. Second-generation CARs incorporated one costimulatory domain, such as CD28 or 4-1BB, thereby improving T-cell expansion, persistence, and cytotoxic function [44,45]. Third-generation CARs contain 2 or more costimulatory domains, such as CD28 combined with 4-1BB or OX40, to further enhance activation and survival signals [41,45,46].
Fourth-generation CAR-T cells, also known as T cells redirected for universal cytokine-mediated killing (TRUCKs), are engineered to secrete cytokines or immune-modulating molecules after antigen recognition [45,47]. Fifth-generation CAR-T-cell designs incorporate additional intracellular signaling modules or gene-editing strategies to improve safety, reduce rejection, and enhance antitumor activity [41,48]. These structural innovations provide the basis for optimizing CAR-T-cell therapy in HCC and other solid tumors [32,48,49]. Figure 2 depicts the structural evolution of chimeric antigen receptor (CAR) T-cell constructs from the first to the fifth generation (Figure 2).
CAR-T-cell therapy has achieved clear clinical success in hematologic malignancies, with studies reporting high remission rates in refractory B-cell malignancies [28–31]. In contrast, the development of CAR-T-cell therapy for solid tumors has been more difficult because tumor-associated antigens are often heterogeneously expressed and may also be present at low levels in normal tissues [32,42,50].
Successful CAR-T-cell therapy for solid tumors requires identification of targets that are highly expressed in tumor cells but limited in essential normal tissues [33,42,50]. Additional barriers include inadequate homing of CAR-T cells to tumor sites, limited penetration into dense tumor tissue, metabolic stress, checkpoint-mediated exhaustion, and suppression by regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and cytokines such as transforming growth factor beta (TGF-beta) [32–35].
Several strategies have been investigated to improve CAR-T-cell activity in solid tumors, including regional infusion, dual-target CAR design, armored CAR-T cells, checkpoint blockade combinations, cytokine engineering, and modification of the TME [32–35,49]. These approaches are particularly relevant to HCC, which develops in a tolerogenic liver environment and frequently coexists with chronic inflammation and cirrhosis [4,7,8].
CAR-T Therapy for Hepatocellular Carcinoma
HCC is characterized by molecular heterogeneity, vascular invasion, high recurrence risk, and an immunologically complex microenvironment [4,7,8,20]. Immune checkpoint inhibitors and antiangiogenic combinations have changed the systemic treatment landscape for advanced HCC, but resistance and limited durable responses remain major challenges [15,16,20,23–25]. CAR-T-cell therapy provides a target-directed approach that may complement existing systemic and locoregional therapies [27,32,42,50].
According to registered clinical studies and published reports, multiple CAR-T-cell strategies for HCC have focused on antigens such as GPC3, CEA, CD133, AFP, EGFRvIII, B7H3, MUC1, NKG2DL, PD-L1/c-Met, CD147, CD44, DR5, MG7, human epidermal growth factor receptor 2 (HER2), TGF-beta, and EpCAM [49,51–88]. The current evidence remains dominated by early-phase trials and preclinical studies, and large randomized trials are still lacking [54,55,61,64,80].
HCC-Associated CAR-T Targets
CEA:
Carcinoembryonic antigen (CEA), also known as CEACAM5, is a tumor-associated antigen expressed in several epithelial malignancies [51]. Anti-CEA CAR-T-cell approaches have been explored using hepatic artery infusion to enhance regional delivery to liver lesions [52]. In a phase Ib study of intraarterial CAR-T-cell therapy combined with selective internal radiation therapy for CEA-positive liver metastases, the approach was feasible and did not produce severe cytokine release syndrome or neurotoxicity [52].
GPC3:
Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan that is overexpressed in many HCC tissues and is associated with tumor progression [53]. GPC3 is one of the most widely investigated targets for CAR-T-cell therapy in HCC [54,55,89,90]. In early-phase clinical studies, GPC3-targeted CAR-T cells demonstrated acceptable safety and preliminary antitumor activity in selected patients with advanced GPC3-positive HCC [54]. Fourth-generation GPC3-targeted CAR-T-cell strategies secreting interleukin 7 (IL-7) and C-C motif chemokine ligand 19 (CCL19) have also been explored to enhance immune cell recruitment and antitumor activity [55].
CD133:
CD133 is a transmembrane glycoprotein expressed in cancer stem-like cells and has been associated with aggressive tumor biology and poor prognosis in HCC [56–60]. CD133-directed CAR-T-cell therapy has been evaluated in patients with advanced malignancies and HCC [61,64]. In a single-arm phase II trial of CD133-directed CAR-T cells in advanced HCC, partial response and stable disease were observed in a subset of patients, with median overall survival and progression-free survival suggesting preliminary clinical activity [64].
AFP:
Alpha-fetoprotein (AFP) is a classical biomarker of HCC and has been investigated as a target for T-cell-based immunotherapy [65]. Because AFP is an intracellular and secreted antigen, AFP-targeted CAR-T-cell strategies rely on recognition of AFP-derived peptide-major histocompatibility complex complexes rather than direct surface antigen binding [65]. Preclinical findings support the feasibility of AFP-MHC complex targeting, although further clinical evidence is needed [65].
EGFRVIII:
Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutant form of epidermal growth factor receptor that has been detected in several malignancies, including HCC [66–68]. EGFRvIII-specific CAR-T cells produced using the piggyBac transposon system inhibited HCC cell growth in vitro and in vivo, supporting EGFRvIII as a potential HCC CAR-T target [69].
B7H3:
B7 homolog 3 (B7H3) is a member of the B7 immunoglobulin superfamily and is overexpressed in several solid tumors [70]. Tandem CAR-T cells targeting CD70 and B7H3 showed potent preclinical activity against multiple solid tumors, suggesting a potential strategy for tumors with heterogeneous antigen expression [70]. Clinical translation of B7H3-targeted CAR-T cells in HCC remains under investigation.
MUC1 AND NKG2DL:
Mucin 1 (MUC1) is a transmembrane glycoprotein involved in tumor progression and immune regulation [71,72]. MUC1 expression has been observed in HCC models, and MUC1-targeted CAR-T-cell approaches have shown antitumor activity in experimental HCC systems [73]. Natural killer group 2 member D ligand (NKG2DL) is another target of interest because NKG2D ligands are frequently induced by cellular stress and malignant transformation [74,75]. NKG2D-based CAR-T cells have eradicated NKG2DL-positive HCC cells in preclinical models [77].
PD-L1/C-MET, CD147, CD44, AND OTHER TARGETS:
Programmed death-ligand 1 (PD-L1) contributes to immune evasion by interacting with programmed death 1 (PD-1) on T cells [78]. Dual-targeting strategies involving PD-L1 and c-Met have been explored as a way to combine tumor targeting with checkpoint-related mechanisms [79]. CD147 is highly expressed in HCC and is associated with invasion, metastasis, and poor prognosis [80–82]. Anti-CD147 CAR-T cells demonstrated antitumor efficacy against HCC in preclinical studies, and inducible CD147-targeted CAR-T designs have been developed to improve controllability [80,86]. CD44 is a cancer stem cell-associated marker, and CD44-targeted CAR-T cells suppressed HCC growth in experimental models [87,88]. Additional targets, including death receptor 5 (DR5), MG7, HER2, TGF-beta, and EpCAM, are being explored in registered studies and preclinical reports [49].
CLINICAL STUDIES OF CAR-T THERAPY IN HCC:
Most clinical studies of CAR-T-cell therapy for HCC are early-phase trials designed to evaluate safety, feasibility, dose escalation, route of administration, and preliminary efficacy [36,54,55,61,64,91]. GPC3 remains the most clinically advanced HCC-related CAR-T target, with published phase I data supporting tolerability and early signs of activity [54,55]. CD133-directed CAR-T-cell therapy has also been evaluated in advanced HCC, with disease stabilization observed in some patients [61,64].
Regional delivery strategies, including hepatic artery infusion, transcatheter arterial infusion, and intratumoral injection, have been used in several trials to increase local exposure and reduce systemic toxicity [51,64]. However, the available clinical evidence remains limited by small sample sizes, heterogeneous trial designs, variable target expression, and incomplete reporting of long-term outcomes [54,55,61,64]. Table 1 summarizes registered clinical studies of CAR-T-cell therapy targeting HCC-related antigens.
Safety, Toxicity, and Barriers to Clinical Translation
CAR-T-cell therapy can be associated with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome, cytopenias, and on-target/off-tumor toxicity [92,93]. In solid tumors, safety concerns are amplified when target antigens are also expressed in normal tissues [32,42,50]. Careful target selection and controllable CAR designs are therefore important for improving the therapeutic index in HCC [80,86].
The TME is a major barrier to CAR-T-cell efficacy in HCC [32–35]. Physical barriers, hypoxia, metabolic stress, immune checkpoint signaling, TGF-beta-mediated suppression, regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages can impair CAR-T-cell trafficking, activation, and persistence [32–35,94]. Antigen heterogeneity and antigen loss can further reduce response durability [49].
Potential solutions include dual- or multi-target CAR constructs, cytokine-armored CAR-T cells, checkpoint-resistant CAR-T cells, hypoxia-responsive designs, regional infusion, and combination therapy with immune checkpoint inhibitors, antiangiogenic agents, targeted therapies, or locoregional treatments [32–35,49,55,89,90,94].
Future Directions
Future development of CAR-T-cell therapy for HCC should prioritize accurate target selection, standardized antigen-expression assessment, and rational trial design. Biomarker-driven enrollment may help identify patients most likely to benefit from target-specific CAR-T-cell therapy [53,54,64,80]. Multi-antigen strategies may reduce antigen escape, whereas inducible or switchable CAR systems may improve safety and controllability [49,80,86].
Combination strategies are also likely to be important. CAR-T-cell therapy may be combined with immune checkpoint inhibitors to counteract T-cell exhaustion, with antiangiogenic agents to improve tumor perfusion and immune infiltration, or with locoregional therapies to enhance antigen release and local immune activation [20,23–25,32–35]. Regional delivery may further improve the balance between efficacy and toxicity in liver tumors [52,64].
Long-term clinical translation will require larger multicenter trials, harmonized toxicity reporting, standardized response assessment, and extended follow-up for delayed adverse events and durability of response [54,55,64,93]. Manufacturing optimization and cost reduction will also be essential for broader clinical application.
Conclusions
CAR-T-cell therapy is an emerging immunotherapeutic strategy for HCC. Recent advances in CAR design, target identification, and early clinical translation have expanded the therapeutic potential of CAR-T cells in this disease. GPC3, CD133, AFP, EGFRvIII, NKG2DL, CD147, and EpCAM are among the most actively investigated HCC-related targets. However, tumor heterogeneity, antigen escape, limited tumor infiltration, and the immunosuppressive TME remain major barriers. Future research should focus on safer CAR engineering, multi-target strategies, rational combination therapies, and well-designed clinical trials to clarify the clinical role of CAR-T-cell therapy in HCC1.
References
1. Siegel RL, Miller KD, Fuchs HE, Jemal A, Cancer statistics, 2022: Cancer J Clin, 2022; 72(1); 7-33
2. Siegel RL, Miller KD, Wagle NS, Jemal A, Cancer statistics, 2023: Cancer J Clin, 2023; 73(1); 17-48
3. Sung H, Ferlay J, Siegel RL, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries: Cancer J Clin, 2021; 71(3); 209-49
4. Llovet JM, Kelley RK, Villanueva A, Hepatocellular carcinoma: Nat Rev Dis Primers, 2021; 7(1); 6
5. Petrick JL, Florio AA, Znaor A, International trends in hepatocellular carcinoma incidence, 1978–2012: Int J Cancer, 2020; 147(2); 317-30
6. Bray F, Ferlay J, Soerjomataram I, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries: Cancer J Clin, 2018; 68(6); 394-424
7. Kulik L, El-Serag HB, Epidemiology and management of hepatocellular carcinoma: Gastroenterology, 2019; 156(2); 477-91e1
8. Yang JD, Hainaut P, Gores GJ, A global view of hepatocellular carcinoma: Trends, risk, prevention and management: Nat Rev Gastroenterol Hepatol, 2019; 16(10); 589-604
9. Sugawara Y, Hibi T, Surgical treatment of hepatocellular carcinoma: Biosci Trends, 2021; 15(3); 138-41
10. Forner A, Reig M, Bruix J, Hepatocellular carcinoma: Lancet, 2018; 391(10127); 1301-14
11. Pinna AD, Yang T, Mazzaferro V, Liver transplantation and hepatic resection can achieve cure for hepatocellular carcinoma: Ann Surg, 2018; 268(5); 868-75
12. Llovet JM, Burroughs A, Bruix J, Hepatocellular carcinoma: Lancet, 2003; 362(9399); 1907-17
13. Llovet JM, Ricci S, Mazzaferro V, Sorafenib in advanced hepatocellular carcinoma: N Engl J Med, 2008; 359(4); 378-90
14. Bruix J, Qin S, Merle P, 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
15. Zhu AX, Finn RS, Edeline J, 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); 940-52
16. El-Khoueiry AB, Sangro B, Yau T, 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
17. Kudo M, Finn RS, Qin S, Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial: Lancet, 2018; 391(10126); 1163-73
18. Abou-Alfa GK, Meyer T, Cheng AL, Cabozantinib in patients with advanced and progressing hepatocellular carcinoma: N Engl J Med, 2018; 379(1); 54-63
19. Zhu AX, Kang YK, Yen CJ, Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial: Lancet Oncol, 2019; 20(2); 282-96
20. 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
21. Zhang DZ, Niu JQClinical advances in targeted therapy and immunotherapy for hepatocellular carcinoma: Zhonghua Gan Zang Bing Za Zhi, 2019; 27(11); 834-37 [in Chinese]
22. Galon J, Bruni D, Tumor immunology and tumor evolution: Intertwined histories: Immunity, 2020; 52(1); 55-81
23. Liu Z, Lin Y, Zhang J, Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma: J Exp Clin Cancer Res, 2019; 38(1); 447
24. Faivre S, Rimassa L, Finn RS, Molecular therapies for HCC: Looking outside the box: J Hepatol, 2020; 72(2); 342-52
25. Sonbol MB, Riaz IB, Naqvi SAA, Systemic therapy and sequencing options in advanced hepatocellular carcinoma: A systematic review and network meta-analysis: JAMA Oncol, 2020; 6(12); e204930
26. Jogalekar MP, Rajendran RL, Khan F, CAR T-Cell-Based gene therapy for cancers: New perspectives, challenges, and clinical developments: Front Immunol, 2022; 13; 925985
27. June CH, O’Connor RS, Kawalekar OU, CAR T cell immunotherapy for human cancer: Science, 2018; 359(6382); 1361-65
28. Brentjens RJ, Davila ML, Riviere I, CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia: Sci Transl Med, 2013; 5(177); 177ra38
29. Kochenderfer JN, Dudley ME, Kassim SH, Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor: J Clin Oncol, 2015; 33(6); 540-49
30. Lee DW, Kochenderfer JN, Stetler-Stevenson M, 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); 517-28
31. Gardner RA, Finney O, Annesley C, Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults: Blood, 2017; 129(25); 3322-31
32. Lindo L, Wilkinson LH, Hay KA, Befriending the hostile tumor microenvironment in CAR T-cell therapy: Front Immunol, 2020; 11; 618387
33. Cadilha BL, Benmebarek MR, Dorman K, Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors: Sci Adv, 2021; 7(24); 5781
34. Füchsl F, Krackhardt AM, Paving the way to solid tumors: challenges and strategies for adoptively transferred transgenic T cells in the tumor microenvironment: Cancers (Basel), 2022; 14(17); 4192
35. Newick K, O’Brien S, Moon E, Albelda SM, CAR T cell therapy for solid tumors: Annu Rev Med, 2017; 68; 139-52
36. Zhou Y, Wei S, Xu M, CAR-T cell therapy for hepatocellular carcinoma: current trends and challenges: Front Immunol, 2024; 15; 1489649
37. Elahi R, Alami Idrissi Y, Saeed A, CAR-T cell therapy in hepatocellular carcinoma: from mechanistic insights to clinical translation: Cancer Treat Rev, 2025; 141; 103046
38. Teoh PJ, Chng WJ, CAR T-cell therapy in multiple myeloma: more room for improvement: Blood Cancer J, 2021; 11(4); 84
39. Marofi F, Rahman HS, Achmad MH, A deep insight into CAR-T cell therapy in non-hodgkin lymphoma: Application, opportunities, and future directions: Front Immunol, 2021; 12; 681984
40. Hudecek M, Sommermeyer D, Kosasih PL, The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity: Cancer Immunol Res, 2015; 3(2); 125-35
41. Elahi R, Khosh E, Tahmasebi S, Esmaeilzadeh A, Immune cell hacking: challenges and clinical approaches to create smarter generations of chimeric antigen receptor T cells: Front Immunol, 2018; 9; 1717
42. Ma S, Li X, Wang X, Current progress in CAR-T cell therapy for solid tumors: Int J Biol Sci, 2019; 15(12); 2548-60
43. Hyllner J, Mason C, Wilmut I, Cells: from Robert Hooke to cell therapy – A 350 year journey: Philos Trans R Soc Lond B Biol Sci, 2015; 370(1680); 20150320
44. Savoldo B, Ramos CA, Liu E, CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients: J Clin Invest, 2011; 121(5); 1822-26
45. Huang R, Li X, He Y, Recent advances in CAR-T cell engineering: J Hematol Oncol, 2020; 13(1); 86
46. Au R, Immunooncology: Can the right chimeric antigen receptors T-cell design be made to cure all types of cancers and will it be covered?: J Pharm (Cairo), 2017; 2017; 7513687
47. Duan D, Wang K, Wei C, The BCMA-targeted fourth-generation CAR-T cells secreting IL-7 and CCL19 for therapy of refractory/recurrent multiple myeloma: Front Immunol, 2021; 12; 609421
48. Roselli E, Faramand R, Davila ML, Insight into next-generation CAR therapeutics: Designing CAR T cells to improve clinical outcomes: J Clin Invest, 2021; 131(2); e142030
49. Qu C, Zhang H, Cao H, Tumor buster – where will the CAR-T cell therapy ‘missile’ go?: Mol Cancer, 2022; 21(1); 201
50. Guo F, Cui J, CAR-T in solid tumors: Blazing a new trail through the brambles: Life Sci, 2020; 260; 118300
51. Han ZW, Lyv ZW, Cui B, The old CEACAMs find their new role in tumor immunotherapy: Invest New Drugs, 2020; 38(6); 1888-98
52. Katz SC, Hardaway J, Prince E, HITM-SIR: Phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA(+) liver metastases: Cancer Gene Ther, 2020; 27(5); 341-55
53. Kaseb AO, Hassan M, Lacin S, Evaluating clinical and prognostic implications of Glypican-3 in hepatocellular carcinoma: Oncotarget, 2016; 7(43); 69916-26
54. Shi D, Shi Y, Kaseb AO, Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: results of phase I trials: Clin Cancer Res, 2020; 26(15); 3979-89
55. Pang N, Shi J, Qin L, IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin: J Hematol Oncol, 2021; 14(1); 118
56. Glumac PM, LeBeau AM, The role of CD133 in cancer: A concise review: Clin Transl Med, 2018; 7(1); 18
57. Schmohl JU, Vallera DA, CD133, selectively targeting the root of cancer: Toxins (Basel), 2016; 8(6); 165
58. Won C, Kim BH, Yi EH, Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma: Hepatology, 2015; 62(4); 1160-73
59. Kohga K, Tatsumi T, Takehara T, Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma: J Hepatol, 2010; 52(6); 872-79
60. Yang XR, Xu Y, Yu B, High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma: Gut, 2010; 59(7); 953-62
61. Wang Y, Chen M, Wu Z, CD133-directed CAR T cells for advanced metastasis malignancies: A phase I trial: Oncoimmunology, 2018; 7(7); e1440169
62. Ho JW, Pang RW, Lau C, Significance of circulating endothelial progenitor cells in hepatocellular carcinoma: Hepatology, 2006; 44(4); 836-43
63. Gao D, Nolan DJ, Mellick AS, Bambino K, Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis: Science, 2008; 319(5860); 195-98
64. Dai H, Tong C, Shi D, Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: A single-arm, open-label, phase II trial: Oncoimmunology, 2020; 9(1); 1846926
65. Liu H, Xu Y, Xiang J, Targeting alpha-fetoprotein (AFP)-MHC complex with CAR T-cell therapy for liver cancer: Clin Cancer Res, 2017; 23(2); 478-88
66. Gan HK, Cvrljevic AN, Johns TG, The epidermal growth factor receptor variant III (EGFRvIII): Where wild things are altered: FEBS J, 2013; 280(21); 5350-70
67. Luo X, Xie H, Long X, EGFRvIII mediates hepatocellular carcinoma cell invasion by promoting S100 calcium binding protein A11 expression: PLoS One, 2013; 8(12); e83332
68. Xu W, Song F, Wang B, The effect of and mechanism underlying autophagy in hepatocellular carcinoma induced by CH12, a monoclonal antibody directed against epidermal growth factor receptor variant III: Cell Physiol Biochem, 2018; 46(1); 226-37
69. Ma Y, Chen Y, Yan L, EGFRvIII-specific CAR-T cells produced by piggyBac transposon exhibit efficient growth suppression against hepatocellular carcinoma: Int J Med Sci, 2020; 17(10); 1406-14
70. Yang M, Tang X, Zhang Z, Tandem CAR-T cells targeting CD70 and B7-H3 exhibit potent preclinical activity against multiple solid tumors: Theranostics, 2020; 10(17); 7622-34
71. Nath S, Mukherjee P, MUC1: A multifaceted oncoprotein with a key role in cancer progression: Trends Mol Med, 2014; 20(6); 332-42
72. Chen W, Zhang Z, Zhang S, MUC1: Structure, function, and clinic application in epithelial cancers: Int J Mol Sci, 2021; 22(12); 6567
73. Jiang Z, Cheng L, Wu Z, Transforming primary human hepatocytes into hepatocellular carcinoma with genetically defined factors: EMBO Rep, 2022; 23(6); e54275
74. Zhang J, Basher F, Wu JD, NKG2D ligands in tumor immunity: Two sides of a coin: Front Immunol, 2015; 6; 97
75. Dhar P, Wu JD, NKG2D and its ligands in cancer: Curr Opin Immunol, 2018; 51; 55-61
76. Kamimura H, Yamagiwa S, Tsuchiya A, Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence: J Hepatol, 2012; 56(2); 381-88
77. Sun B, Yang D, Dai H, Eradication of hepatocellular carcinoma by NKG2D-based CAR-T cells: Cancer Immunol Res, 2019; 7(11); 1813-23
78. Cha JH, Chan LC, Li CW, Mechanisms controlling PD-L1 expression in cancer: Mol Cell, 2019; 76(3); 359-70
79. Xiong C, Mao Y, Wu T, Optimized expression and characterization of a novel fully human bispecific single-chain diabody targeting vascular endothelial growth factor165 and programmed death-1 in pichia pastoris and evaluation of antitumor activity in vivo: Int J Mol Sci, 2018; 19(10); 2900
80. Tseng HC, Xiong W, Badeti S, Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma: Nat Commun, 2020; 11(1); 4810
81. Li Y, Xu J, Chen L, HAb18G (CD147), a cancer-associated biomarker and its role in cancer detection: Histopathology, 2009; 54(6); 677-87
82. Lu M, Wu J, Hao ZW, Basolateral CD147 induces hepatocyte polarity loss by E-cadherin ubiquitination and degradation in hepatocellular carcinoma progress: Hepatology, 2018; 68(1); 317-32
83. Bian H, Zheng JS, Nan G, Randomized trial of [131I] metuximab in treatment of hepatocellular carcinoma after percutaneous radiofrequency ablation: J Natl Cancer Inst, 2014; 106(9); dju239
84. Chen H, Nan G, Wei D, Hepatic artery injection of (131)I-metuximab combined with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: A prospective nonrandomized, multicenter clinical trial: J Nucl Med, 2022; 63(4); 556-59
85. Xu J, Shen ZY, Chen XG, A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation: Hepatology, 2007; 45(2); 269-76
86. Zhang RY, Wei D, Liu ZK, doxycycline inducible chimeric antigen receptor T cells targeting CD147 for hepatocellular carcinoma therapy: Front Cell Dev Biol, 2019; 7; 233
87. Chen C, Zhao S, Karnad A, Freeman JW, The biology and role of CD44 in cancer progression: Therapeutic implications: J Hematol Oncol, 2018; 11(1); 64
88. Wang H, Ye X, Ju Y, Minicircle DNA-mediated CAR T cells targeting CD44 suppressed hepatocellular carcinoma both in vitro and in vivo: Onco Targets Ther, 2020; 13; 3703-16
89. Makkouk A, Yang XC, Barca T, Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma: J Immunother Cancer, 2021; 9(12); e003441
90. Li D, Li N, Zhang YF, Persistent polyfunctional chimeric antigen receptor T cells that target glypican 3 eliminate orthotopic hepatocellular carcinomas in Mice: Gastroenterology, 2020; 158(8); 2250-65e20
91. Wei J, Guo Y, Wang Y, Clinical development of CAR T cell therapy in China: 2020 update: Cell Mol Immunol, 2021; 18(4); 792-804
92. Sterner RM, Sakemura R, Cox MJ, GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts: Blood, 2019; 133(7); 697-709
93. Lee DW, Santomasso BD, Locke FL, ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells: Biol Blood Marrow Transplant, 2019; 25(4); 625-38
94. He H, Liao Q, Zhao C, Conditioned CAR-T cells by hypoxia-inducible transcription amplification (HiTA) system significantly enhances systemic safety and retains antitumor efficacy: J Immunother Cancer, 2021; 9(10); e002755
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