Published online Oct 27, 2022. doi: 10.4254/wjh.v14.i10.1862
Peer-review started: July 4, 2022
First decision: August 13, 2022
Revised: July 20, 2022
Accepted: October 3, 2022
Article in press: October 3, 2022
Published online: October 27, 2022
Processing time: 114 Days and 23.7 Hours
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and its incidence continues to increase. Despite improvements in both medical and surgical therapies, HCC remains associated with poor out
Core Tip: Hepatocellular carcinoma (HCC) is associated with high rates of recurrence and mortality. Approximately 50% of the patients require systemic therapies, traditionally consisting of tyrosine kinase inhibitors, with poor outcomes. Recently, immune checkpoint inhibitors have revolutionized the management of HCC, providing new therapeutic options. Despite these major advances, the different factors involved in poor clinical responses and molecular pathways of escape following use of these therapies remain unclear. Other immune strategies, such as adoptive T-cell transfer, vaccination, virotherapy, and combinations of immunotherapy with other systemic or local treatments, are under evaluation.
- Citation: Cassese G, Han HS, Lee B, Lee HW, Cho JY, Panaro F, Troisi RI. Immunotherapy for hepatocellular carcinoma: A promising therapeutic option for advanced disease. World J Hepatol 2022; 14(10): 1862-1874
- URL: https://www.wjgnet.com/1948-5182/full/v14/i10/1862.htm
- DOI: https://dx.doi.org/10.4254/wjh.v14.i10.1862
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with an estimated global incidence rate of 9.3 per 100000 persons per year and a corresponding mortality rate of 8.5[1]. While the majority of cases are in Eastern Asia, HCC incidence is widely increasing in northwestern Europe as well as in North America. HCC is also the fastest growing cause of cancer-related deaths in US males, tripling in both incidence and mortality rates[2]. The primary risk factors for HCC include underlying cirrhosis (independent of etiology) and chronic infection with hepatitis B virus or hepatitis C virus[3]. Since diabetes, obesity, and metabolic syndrome are also hypothesized to be risk factors associated with the development of metabolic cirrhosis, HCC is expected to become progressively more concerning as a health problem in the near future[4].
HCC is associated with a poor prognosis. A 5-year overall survival (OS) of 50–70% is only attained if the tumor is still resectable, owing to advances in both surgical and medical therapy[5]. Surgical tr
Accordingly, liver resection is considered the first-line treatment for HCC in patients with com
Trans-arterial chemoembolization (TACE) is the treatment of choice for patients with a suitable performance status[11]. Medical therapy is the only viable option for cases with disseminated disease or when other therapies are not feasible. However, HCC is notoriously resistant to chemotherapy and other systemic treatment modalities[12]. To date, systemic therapy is mainly based on the use of sorafenib, a multitargeted kinase inhibitor that improves survival by only 2.3-2.8 mo[13]. Indeed, the global median survival for patients with unresectable HCC is less than 1 year, highlighting the need for novel therapies to treat this disease.
Owing to an improved understanding of the molecular pathways of HCC carcinogenesis, other molecularly targeted approaches are under investigation. However, the intrinsic drug-metabolizing properties of the liver and other factors likely contribute to the limited efficacy of chemotherapeutics in the treatment of HCC[14]. In this review, we summarize novel immunotherapeutic approaches in HCC, reporting the latest evidence, analyzing their main limitations, and summarizing future perspectives that might overcome these drawbacks.
Due to its physiological function, the liver has a peculiar and complex anti-inflammatory immune environment that develops tolerance to harmless foreign molecules, such as food antigens[15]. Kupffer cells (KCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs) are the main mediators of this tolerogenic process[16]. KCs produce inhibitory cytokines interleukin 10 (IL-10) and prostaglandins and promote the activation of regulatory T cells (Treg)[17]. HSCs produces hepatocyte growth factor (HGF), that induces the accumulation of Treg cells inside the liver and promotes T-cell apoptosis through programmed death ligand 1 (PDL1) expression[18,19]. LSECs also play a fun
The complex physiological immune-tolerating microenvironments of the liver are altered during the formation and progression of HCC. A progressively and persistently downregulated immune gene profile has been identified to occur during HCC progression, which leads to lower tumor immunity in advanced stages of the disease, together with a physical barrier made of collagen and other matrix proteins that protect tumoral cells[23]. Therefore, an interesting strategy could be to use therapeutic compounds to disrupt collagen and promote intratumoral infiltration by CD8+ lymphocytes trapped in the peritumoral zone[24]. Different approaches to modulating this complex immune microsystem are desirable in combination with immunotherapies for HCC.
The tumor microenvironment (TME) of HCC is the result of complex interactions among hepatic non-parenchymal resident cells, tumor cells, immune cells, and tumor-associated fibroblasts[25]. The TME has important effects on the presence and activity of all signaling molecules, such as cytokines and chemokines, as well as other paracrine factors[26]. This complex cellular interplay has a substantial influence on tumor immune evasion, affecting both innate and adaptive immune responses and often leading to high levels of dysfunctional tumor-infiltrating lymphocytes (TILs) and natural killer (NK) cells[27,28].
The peritumoral environment at the forefront of HCC development is also important. KCs at this stage show higher levels of PDL1, and hyperactivation of HSCs in this TME is associated with a poor prognosis[29,30]. Similarly, PDL1 expression is higher in CD8+ T cells, which is associated with a higher risk of cancer recurrence, metastasis, and death[31]. Other molecules involved in the immune checkpoint have been identified in HCC and have been shown to correlate with poor prognosis, such as T-cell immunoglobulin, mucin-domain-containing molecule-3 (Tim-3), and lymphocyte-activation gene 3 in TILs and tumor-associated macrophages (TAM)[32].
Several molecular mechanisms of immune evasion have been described in HCC, derived from the alteration of different signaling pathways, although much remains to be explored.
TGF-β is abundant in the HCC TME and can be produced by tumor cells, TAMs, and Treg cells[25,33]. TGF-β can reduce or eliminate antitumor responses by blocking T-cells and NK cells, inhibiting APC cells and TAMs, and activating Tregs[34-36]. High TGF-β expression has been shown to be associated with poor prognosis in HCC patients, and circulating levels are associated with clinical response to sorafenib and pembrolizumab[37,38].
Pro-inflammatory cytokines such as tumor necrosis factor and IL-1 are significantly downregulated in the HCC TME and are associated with increased levels of immunosuppressive cytokines, resulting in immune response dysfunction (IL-4, IL-5, IL-8, and IL-10)[23]. This has been associated with poor prognosis and worse clinical outcomes in several cancer types, including HCC[39]. Another pro-inflammatory cytokine, type I interferon (IFN), can activate the immune response; however, it can also trigger anti-inflammatory signals through the production of IL-10[40]. IL-10 is upregulated in HCC and is produced by TAMs and Treg cells. It can impair the capacity of APCs to recruit T cells and promote the upregulation of PDL1 in monocytes[41]. Furthermore, IL-10 Levels are associated with the number of myeloid-derived suppressor cells (MDSC)[42]. Representing the complexity of the TME, low IFNγ levels are associated with a worse prognosis in HCC[43].
Chemokines also play a fundamental role in recruiting Tregs via chemokine receptor 6 (CCR6) and chemokine ligand 20 (CCL20)[44]. The level of both Treg cells and TAMs in the liver is associated with poor prognosis in HCC[45,46]. A rare recently discovered immunosuppressive cell is represented by the T helper 17 cells, that produce high levels of PD1and inhibit NK cell function. Then there are the hepatic neutrophils that can recruit macrophages and Treg cells[47,48].
Vascular endothelial growth factor (VEGF) is a soluble molecule produced by tumor cells and the surrounding stroma[49]. It is known to promote tumor angiogenesis, but it can also act as an immune modulator by inhibiting liver APCs and activating MDSCs and Treg cells[50]. This immunomodulatory action of VEGF inhibitors may play a role into their anti-tumor activity. The presence of many possible immunoregulatory targets in the HCC TME has stimulated the investigation of different immunotherapies in HCC, some of which have been shown to be effective for other malignancies.
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies directed against extracellular ligands involved in the suppression of antitumor immune responses. These proteins are expressed by both cancer cells and the immune system cells. To date, only two categories of molecular targets have been examined in clinical trials, PD-1 and CTLA-4, and only two checkpoint inhibitors have been approved for use in HCC by the United States Food and Drug Association (FDA)[51,52], while many more promising targets are being investigated.
Nivolumab is a human anti-PD-1 IgG4 monoclonal antibody targeting PD-1, currently used as a second-line therapy for HCC after approval by the FDA in 2017. Checkmate 040, a phase I/II dose escalation and expansion trial, showed substantial tumor reduction and good tolerability in HCC patients. In the Checkmate040 study, patients showed a median OS of 15 mo (95%CI: 9.6-20.2), with an objective response rate (ORR) of 15% (95%CI: 6-28)[53]. The median duration of response to nivolumab among the 48 patients was 17 mo (95%CI, 6-24 mo), with a 2-year survival rate higher than 80%[53]. As an unexpected result, patients with PD-1- and PD-L1 expression showed better survival outcomes, with a median OS of 28.1 mo (95%CI: 18.2-n.a.) vs. 16.6 mo in the group with low PD-L1 expression (95%CI: 14.2-20.2).
CheckMate 459, a phase III trial, comparied the efficacy of nivolumab vs sorafenib as a first-line treatment in 743 HCC patients[54]. In the Nivolumab cohort, the OS outcomes were not statistically significant (median survival 16.4 vs 14.7 mo, HR 0.85; P = 0.07). However, in this study, patients with PD-L1 expression > 1% in the nivolumab arm had a significantly higher ORR (28.2% vs 12.2%). Furthermore, the rate of grade 3 or 4 adverse events in nivolumab arm was only 22%, compared to 49% after sorafenib[54]. Currently, other clinical trials are investigating the role of nivolumab for HCC, either as monotherapy or in combination with other modalities (Tables 1 and 2).
Trial | Included population | Immunotherapy regimen | Target | Control arm | Primary outcome | Sample size |
CHECKMATE-9DX (NCT03383458) | Patients at high risk of recurrence after resection or ablation | Nivolumab | PD-1 | Placebo | RFS | 530 |
KEYNOTE-937 (NCT03867084) | Patients with complete radiological response after resection or ablation | Pembrolizumab | PD-1 | Placebo | RFS, OS | 950 |
EMERALD-2 (NCT03847428) | Patients at high risk of recurrence after resection or ablation | Durvalumab plus bevacizumab anddurvalumab plus placebo | PD-L1 | Placebo plus placebo | RFS | 888 |
IMBRAVE-050 (NCT04102098) | Patients at high risk of recurrence after resection or ablation | Atezolizumab plus bevacizumab | PD-L1 | Active surveillance | RFS | 662 |
Trial | Immunotherapy regimen | Target | Control arm | Primary outcome | Sample size |
RATIONALE-301 (NCT03412773 | Tislelizumab | PD-1 | Sorafenib | OS | 674 |
CHECKMATE-9DW (NCT04039607) | Nivolumab plus ipilimumab | PD-1 | Sorafenib or Lenvatinib | OS | 650 |
COSMIC-312 (NCT03755791) | Atezolizumab plus cabozantinib | PD-L1/Tyrosine Kinase | Cabozantinib or Sorafenib | PFS, OS | 740 |
ORIENT-32 (NCT03794440) | Sintilimab plus IBI305 | PD1/VEGF | Sorafenib | OS, ORR | 595 |
LEAP-002 (NCT03713593) | Lenvatinib plus pembrolizumab | VEGF-R/PD-1 | Lenvatinib plus placebo | PFS, OS | 750 |
HIMALAYA (NCT03298451) | Durvalumab plus tremelimumab or durvalumab | PD-L1/CTLA4 | Sorafenib | OS | 1504 |
PHOCUS (NCT02562755) | Pexa-Vec plus sorafenib | Thymidine kynase | Sorafenib | OS | 459 |
LEAP-012 (NCT04246177) | TACE plus pembrolizumab plus lenvatinib | PD-1 | TACE plus placebo plus placebo | PFS, OS | 950 |
CHECKMATE-74W (NCT04340193) | TACE plus nivolumab plus ipilimumab | PD-1 | TACE plus nivolumab plusplacebo or TACE plus placebo plus placebo | TTTP, OS | 765 |
EMERALD-1 (NCT03778957) | TACE plus durvalumab plus; Bevacizumab or TACE plus durvalumab plus placebo | PD-L1/VEGF | TACE plus placebo plus placebo | PFS | 710 |
TACE-3 (NCT04268888) | DEB TACE plus nivolumab | PD-1 | DEB TACE | OS | 522 |
Pembrolizumab is an anti-PD-1 IgG4 antibody approved by the FDA in 2018 as a second-line systemic therapy for HCC after sorafenib. A phase II trial, KEYNOTE-224, showed high efficacy and tolerability of pembrolizumab in HCC patients with a significant gain of survival (HR, 0.78; P = 0.023), although it did not meet the prespecified statistical threshold[55]. The ORR was 17% (95%CI: 11-26), while1% of the patients showed a complete response to the treatment and 16% experienced a partial response. The median OS was 12.9 mo (95%CI: 9.7-15.5), and the median progression-free survival (PFS) was 4.9 mo (95%CI: 3.4-7.2). Sixty-two percent of patients showed a good disease control (95%CI: 52-71), while the 25% of patients experienced grade 3 or 4 adverse events, with 1 death[55]. More evidences are expected from KEYNOTE-240 and KEYNOTE-394, two phase III trials investigating the role of Pembrolizumab, that are still ongoing.
Similarly, trials evaluating the association between pembrolizumab and other treatments are ongoing. A phase Ib trial showed promising antitumor activity of the combination of pembrolizumab with lenvatinib (a multiple kinase inhibitor against VEGF receptors) as a first-line treatment in patients with unresectable HCC[56]. Furthermore, a phase III trial has investigated the safety and efficacy of pembrolizumab in combination with lenvatinib, while the role of pembrolizumab alone as adjuvant therapy after RFA or radiotherapy is still under evaluation (Tables 1 and 2).
Atezolizumab is an engineered IgG1 monoclonal antibody targeting PD-L1 and was recently approved by the FDA and European Medicines Agency in combination with bevacizumab as a first-line treatment for unresectable HCC. In the open-label phase III IMbrave150 clinical trial, 501 patients were randomly assigned at a ratio of 2:1 to receive atezolizumab plus bevacizumab or sorafenib[57]. The combination of atezolizumab and bevacizumab showed significantly higher 12-months OS, 67.2% (95%CI: 61.3-73.1) vs 54.6% (95%CI: 45.2-64.0), respectively, with 52% and 40% of patients surviving at 18 months, respectively. Similarly, the median PFS was improved at 6.8 months (95%CI: 5.7-8.3) vs 4.3 months (95%CI: 4.0-5.6), respectively (P < 0.001).
Further studies investigating the combination of atezolizumab with other treatments are ongoing (Table 2). In particular, the COSMIC-312 phase III study tested atezolizumab plus cabozantinib (an oral tyrosine kinase inhibitor against VEGFR, FLT-3, MET, AXL, KIT, Tie-2, and RET) vs sorafenib as first-line therapy. Two phase III studies are enrolling patients to receive atezolizumab plus bevacizumab in combination with TACE or adjuvant therapy after surgery of RFA. Finally, results from several studies investigating other anti-PD-1 antibodies, such as tislelizumab compared to sorafenib, and anti-PD-L1 antibodies, such as durvalumab or avelumab, are expected (Table 2).
The development of vaccines against different types of cancer aims to enhance existing tumor-specific responses. Due to altered T cell activity in the HCC TME, vaccine therapy is usually investigated in combination with ICI or other therapies[58]. Although the first HCC vaccines were shown to be safe and have immunologic effects, their clinical efficacy is still limited, possibly because of immunological tolerance to self-antigens that causes them to not be completely tumor-specific[59,60]. Thus, new strategies are currently under investigation.
Alpha-fetoprotein (AFP) is a 70-kDa protein expressed during fetal development and in the adult liver. Serum AFP levels are usually not detectable in the adult. However, AFP levels increase in approximately 70% of HCC cases, allowing for its use as a biomarker[61,62]. Butterfield et al[63] constructed a human AFP-expressing replication-deficient adenovirus as a new target for T-cell-based immunotherapy. AFP-based therapies have been evaluated in phase I/II trial with two patients with HCC who had an AFP-expressing tumor and who completed a previous treatment for HCC, and their tolerability and safety were confirmed. Additionally, both patients experienced high levels of AFP-specific CD8+ T cells, further confirming their preexisting immunity[64]. Further studies are required to confirm these results.
Multidrug resistance-associated protein 3 (MRP3) is a carrier-type protein that is highly expressed in several human cancers, including HCC[65]. Interestingly, MRP3 is also associated with resistance to sorafenib toxicity in HCC cells[66]. The safety and the immune response to the vaccine based on an MRP3-derived peptide (MRP3765) were tested in a phase I study involving 12 HLA-A24-positive HCC patients[67]. The vaccine showed a good safety profile, with an immune response in 72.7% of the treated cases and a median OS of 14.0 mo (95%CI: 9.6-18.5). OS was notably better than in patients undergoing hepatic arterial infusion chemotherapy without the MRP3 vaccination (median OS 12.0 12.6 mo)[68].
HCC cells sometimes overexpress proteins relative to the surrounding healthy tissue, as is the case for glypican-3 (GPC3)[69]. Therefore, the GPC3-derived peptide vaccine was tested and reported as safe in 33 patients with advanced HCC in a phase I clinical study, showing good results in terms of GPC3-specific immune response[70]. However, only 1 patient developed a partial response, while 19 patients had stable disease. Interestingly, another phase II study investigating the GPC3-derived vaccine as adjuvant therapy showed significantly lower recurrence rates than with surgery alone after 1 year (52.4% vs 61.9%, P = 0. 387) and 2 years (24% vs 48%, P = 0.047)[71].
Oncolytic viruses are viral units engineered to obtain direct lysis of tumor cells, releasing soluble cancer peptides to induce antitumor neoantigen-specific cytotoxic T lymphocyte responses[72]. A phase II study (NCT00554372) assessed the safety of two doses of JX-594 (Pexa-Vec, by testing both low dose or high dose in 30 patients with HCC. All patients experienced dose-dependent flu-like syndrome with fever, rigor, and vomiting within the first few days[73]. Furthermore, when tested as a second-line treatment, there was no significant survival difference when compared to the standard of care (4.2 vs 4.4 mo, 95%CI: 0.78-1.80; P = 0.428)[74]. Other schemes are currently being tested.
DCs can be activated with a specific antigen in vitro and then injected into patients to enhance the immune response. Wang et al[75] obtained encouraging antitumor effects in murine models treated with DCs activated by tumor cell lysate. A good tolerability profile was reported after a phase I study testing autologous DCs on 10 patients with cholangiocarcinoma or HCC, and after a phase II clinical trial with 35 patients using DCs[76]. Interestingly, DC infusion enhanced a stronger tumor-specific immune responses in combination with TACE, than TACE alone, even if without improved survival outcomes[77]. However, further clinical trials are warranted.
New York esophageal squamous cell carcinoma-1 (NY-ESO-1) is a promising target antigen owing to its low expression in healthy tissue[78]. A specific CD8+ T cell response to NY-ESO-1b has been reported in 48% of patients with HCC expressing NY-ESO-1 mRNA and HLA-A2[28]. Furthermore, there was a correlation between such response and patient survival. However, no studies have yet been conducted to investigate the clinical response to NY-ESO-1 vaccines in patients with HCC.
Adoptive cell therapy (ACT) is a passive therapy in which lymphocytes are activated and/or expanded ex vivo, and then re-injected into the patient[79]. The treated cells include lymphokine-activated killer (LAK) cells, cytokine-induced killer (CIK) cells, NK cells, TILs, and redirected peripheral blood T cells. These latter cells are genetically programmed to recognize and attack tumor cells.
An individual’s own T cells can be engineered to recognize tumor cell surface proteins and, in turn, cause cancer cell death, as demonstrated by approximately six chimeric antigen receptor T cell (CAR T cell) therapies already approved by the FDA since 2017 (all of them for blood cancers). A similar effect was observed by targeting GPC3-positive HCC cells in vitro and in mice[80,81]. Takayama et al[82] published excellent results from a trial of 150 patients who were randomly assigned to receive adjuvant adoptive immunotherapy or no treatment. After a median follow-up of 4.4 years, adoptive immunotherapy decreased recurrence rates by 18% compared with that in controls, with a shorter time to first recurrence [33% (95%CI: 22-4) vs 48% (95%CI: 37-59) at 3 years; 22% (95%CI: 11-34) vs 38% (95%CI: 22-54) at 5 years; P = 0.008]. The immunotherapy group had a significantly longer recurrence-free survival (P = 0.01) and disease-specific survival (P = 0.04). Several phase I and phase II clinical studies are currently evaluating CAR-GPC3 T-cell therapy alone or in combination with fludarabine, cyclophosphamide, or other treatment options.
CIK cells are a heterogeneous population of effector CD3+CD56+ NK cells expanded in vitro from peripheral blood mononuclear cells. They are used as pharmacological tools for cancer immunotherapy because they exhibit MHC-unrestricted, safe, and effective antitumor activity. Firsts attempts to develop ACT for HCC were not able to reach the clinical stage owing to the technological complexity and to the low efficacy. A phase II study of 127 patients and a phase III study of 200 patients, in which CIK cells were tested as adjuvant therapy and compared with no adjuvant therapy, showed improved DFS after CIK immunotherapy, although the increase in OS was not statistically significant[83]. Improved OS was observed only in patients diagnosed with tumors > 5 cm in size (P = 0.0002). Furthermore, the com
TILs can also be created from fresh tumor tissue to produce tumor-reactive expanding cells, screened on the basis of the ability to recognize autologous tumor cells, and further expanded to obtain several billion active cells[86]. The safety and feasibility of adjuvant TIL therapy were demonstrated in a phase I trial on HCC patients[87]. Current challenges include the capability of further expand tumor-specific T cells and scaling up the manufacturing process.
Locoregional therapies can be a strong ally in the immunologic war against HCC, owing to several advantages. Their relatively easy accessibility makes HCC an ideal target for local interventions, such as thermal ablations or intra-arterial therapies, and image-guided interventions are a common practice in this setting of patients. Therefore, these approaches can intratumorally deliver immunostimulant agents, allowing not only more potent immunological responses but also potentially decreasing toxicity. Indeed, such agents are often quite toxic when administered systemically, causing sepsis-like cytokine release syndrome and systemic inflammation[88]. Thermal ablation has been shown to activate immune responses and T cell infiltration in HCC[89]. Furthermore, to obtain stronger immune stimulation, different locoregional therapies can be combined sequentially or simultaneously with systemic immunotherapy[90].
Promising results were obtained from the combination of thermal ablation or TACE plus tremelimumab in patients with advanced HCC, with a reported response rate of 26%, a disease control rate of 89%, an OS of 12.3 mo, and 45% of the stabilizations lasting longer than 6 mo[91]. These encouraging data have prompted new clinical trials combining durvalumab/tremelimumab with TACE or RFA, and these trials are ongoing.
The combination of multiple immunotherapies could be another option to overcome the limitations of single treatments. Although this approach could increase the risk of high-grade adverse events, the initial results are encouraging. A combination of nivolumab (NIVO) and ipilimumab (IPI) was tested as a second-line therapy after sorafenib. Following treatment with this combination, patients showed an ORR twice that of the NIVO mono-treated patients (31% and 14%, respectively). Thirty-seven percent of the patients had grade 3-4 treatment-related adverse events, but only 5% had an event leading to therapy discontinuation[92]. Similar results were reported in another study in which nivolumab was tested with cabozantinib (CABO) and ipilimumab, both as double and triple therapies. The median PFS was 5.5 mo for patients in the NIVO + CABO and 6.8 mo for those in the NIVO + IPI + CABO groups, while the median OS was not reached. However, the triple combination led to grade 3-4 treatment-related adverse events in 71% of patients, with 20% discontinuing therapy[23]. Similarly, a phase II trial investigating the safety and efficacy of a combination of durvalumab and tremelimumab is currently recruiting patients.
Immune checkpoint inhibitors can also be combined with oncolytic viruses; this strategy has been tested in several ongoing randomized trials, but without published results. Another study investigated the combination of activated T cell transfer (ATVAC) with an autologous tumor lysate-pulsed DC vaccine as an adjuvant therapy in HCC patients, showing an improved median PFS of 24.5 mo (95%CI: 7.8-41.2) and OS of 97.7 mo (95%CI: 48.6-146.7), compared to a median PFS of 12.6 mo (95%CI: 6.9-18.3) and OS of 41.0 mo (95%CI: 16.3-65.8) of the other group. No adverse events of grade 3 or more were observed[93]. These encouraging results need to be confirmed in future studies.
As previously discussed, several trials have shown encouraging results in certain subgroups of HCC patients, although the overall outcomes have not improved much. Identification of patient subsets that would benefit from ICI therapy should be a mainstay of current cancer research. Indeed, the identification of the best candidates for immunotherapies and combination therapies can play a fundamental role not only in achieving the best results but also in saving a substantial amount of funding and healthcare resources. At the same time, a better understanding of patient characteristics could help to avoid related toxicities.
Some characteristics of the patients in the KEYNOTE-240 and CheckMate 459 trials have already been reported, identifying Asian patients and those with AFP levels > 200 ng/mL as the patient groups showing the best outcomes[54]. The latter study also showed a better OS among patients with vascular invasion or extrahepatic disease. In the IMbrave150 trial, OS and PFS were worse in patients with a non-viral etiology, high AFP levels, no macro-vascular invasion, and extrahepatic disease[57].
The genetic features of HCC have been identified using next-generation sequencing (NGS), and several biomarkers have been identified as useful for selecting the best candidates for new targeted therapies. NGS analysis detected ten patients with WNT/β-catenin mutations that did not respond to anti–PD-1 or anti–PD-L1drugs, while 50% of CTNNB1 WT cases showed a response[94]. The WNT/β-catenin mutation was also correlated to lower median PFS (2.0 vs 7.4 mo; 95%CI: 2.9-28.8; P < 0.0001) and OS (9.1 vs 15.2 mo; 95%CI: 0.76-8.7; P = 0.11) than WNT/β-catenin wild type. Further studies are needed to determine the clinical implications of NGS in HCC therapy.
In conclusion, HCC is a widely studied yet challenging disease. Systemic therapies have shown modest results; however, due to tremendous improvements in basic molecular research on anti-tumor immune responses in the TME, a new class of molecular therapies is emerging and changing the HCC therapeutic landscape. Several clinical trials are ongoing, providing hope for an epochal turning point. In our opinion, the development of synergies between immunotherapies and locoregional or radical therapies is likely to be key in the future of HCC therapy. Similarly, another area where a major shift in HCC management may arise is the role of immunotherapy in adjuvant therapy. In fact, immunotherapy used in an adjuvant setting after surgery showed promising results, affecting recurrence rates, which represents a major challenge following surgical therapy. These results suggest the usefulness of immunotherapy, even in early stages, such as in patients undergoing tumor resection or ablation. Importantly, technological advances and recent evidence have also paved the way for the identification of molecular mechanisms involved in sensitivity and resistance to individual agents or combinations, helping advance the era of personalized medicine. We are convinced that these findings may help in the adoption of and adaptation to different types of therapies for individual patients in the near future. Considering the speed and breadth of discoveries in this field, efforts should be made to embed correlative research studies in every new clinical trial.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country/Territory of origin: South Korea
Peer-review report’s scientific quality classification
Grade A (Excellent): A
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Papadopoulos N, Greece; Shen YH, China; Zimmitti G, Italy S-Editor: Liu JH L-Editor: A P-Editor: Liu JH
1. | McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology. 2021;73 Suppl 1:4-13. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 820] [Cited by in F6Publishing: 1033] [Article Influence: 344.3] [Reference Citation Analysis (1)] |
2. | Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27:1485-1491. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1196] [Cited by in F6Publishing: 1301] [Article Influence: 86.7] [Reference Citation Analysis (0)] |
3. | El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557-2576. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 3846] [Cited by in F6Publishing: 4162] [Article Influence: 244.8] [Reference Citation Analysis (2)] |
4. | Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 2010;42 Suppl 3:S206-S214. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 367] [Cited by in F6Publishing: 397] [Article Influence: 28.4] [Reference Citation Analysis (0)] |
5. | Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1343] [Cited by in F6Publishing: 2921] [Article Influence: 973.7] [Reference Citation Analysis (1)] |
6. | Cassese G, Han HS, Al Farai A, Guiu B, Troisi RI, Panaro F. Future remnant liver optimization: preoperative assessment, volume augmentation procedures and management of PVE failure. Minerva Surg. 2022;77:368-379. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1] [Cited by in F6Publishing: 9] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
7. | Cassese G, Han HS, Lee B, Lee HW, Cho JY, Troisi R. Leaping the Boundaries in Laparoscopic Liver Surgery for Hepatocellular Carcinoma. Cancers (Basel). 2022;14. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 11] [Cited by in F6Publishing: 9] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
8. | Cassese G, Han HS, Lee B, Lee HW, Cho JY, Troisi RI. The role of minimally invasive surgery in the treatment of HCC. Hepatoma Res. 2022;8:26. [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 5] [Reference Citation Analysis (0)] |
9. | Cassese G, Han HS. Minimally invasive surgery for HCC. Hepatoma Res. 2022;8:24. [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 3] [Reference Citation Analysis (0)] |
10. | Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301-1314. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2800] [Cited by in F6Publishing: 3664] [Article Influence: 610.7] [Reference Citation Analysis (5)] |
11. | European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018;69:182-236. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 3934] [Cited by in F6Publishing: 5330] [Article Influence: 888.3] [Reference Citation Analysis (0)] |
12. | Siegel AB, Olsen SK, Magun A, Brown RS Jr. Sorafenib: where do we go from here? Hepatology. 2010;52:360-369. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 77] [Cited by in F6Publishing: 86] [Article Influence: 6.1] [Reference Citation Analysis (0)] |
13. | 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;359:378-390. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 9016] [Cited by in F6Publishing: 9777] [Article Influence: 611.1] [Reference Citation Analysis (1)] |
14. | Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. Oncoimmunology. 2012;1:48-55. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 118] [Cited by in F6Publishing: 122] [Article Influence: 40.7] [Reference Citation Analysis (0)] |
15. | Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009;27:147-163. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 686] [Cited by in F6Publishing: 707] [Article Influence: 47.1] [Reference Citation Analysis (0)] |
16. | Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18:525-543. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 264] [Cited by in F6Publishing: 657] [Article Influence: 219.0] [Reference Citation Analysis (0)] |
17. | Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005;65:2457-2464. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 452] [Cited by in F6Publishing: 466] [Article Influence: 24.5] [Reference Citation Analysis (0)] |
18. | Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, Lu L, Qian S. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology. 2004;40:1312-1321. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 216] [Cited by in F6Publishing: 235] [Article Influence: 11.8] [Reference Citation Analysis (0)] |
19. | Ichikawa S, Mucida D, Tyznik AJ, Kronenberg M, Cheroutre H. Hepatic stellate cells function as regulatory bystanders. J Immunol. 2011;186:5549-5555. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 90] [Cited by in F6Publishing: 102] [Article Influence: 7.8] [Reference Citation Analysis (0)] |
20. | Shetty S, Lalor PF, Adams DH. Liver sinusoidal endothelial cells - gatekeepers of hepatic immunity. Nat Rev Gastroenterol Hepatol. 2018;15:555-567. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 184] [Cited by in F6Publishing: 285] [Article Influence: 47.5] [Reference Citation Analysis (0)] |
21. | Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol. 2006;12:7413-7420. [PubMed] [DOI] [Cited in This Article: ] [Cited by in CrossRef: 315] [Cited by in F6Publishing: 324] [Article Influence: 18.0] [Reference Citation Analysis (1)] |
22. | Streba LA, Streba CT, Săndulescu L, Vere CC, Mitruţ P, Cotoi BV, Popescu LN, Ion DA. Dendritic cells and hepatocellular carcinoma. Rom J Morphol Embryol. 2014;55:1287-1293. [PubMed] [Cited in This Article: ] |
23. | Kole C, Charalampakis N, Tsakatikas S, Vailas M, Moris D, Gkotsis E, Kykalos S, Karamouzis MV, Schizas D. Immunotherapy for Hepatocellular Carcinoma: A 2021 Update. Cancers (Basel). 2020;12. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 55] [Cited by in F6Publishing: 79] [Article Influence: 19.8] [Reference Citation Analysis (0)] |
24. | Wu XZ, Chen D, Xie GR. Extracellular matrix remodeling in hepatocellular carcinoma: effects of soil on seed? Med Hypotheses. 2006;66:1115-1120. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 32] [Cited by in F6Publishing: 34] [Article Influence: 1.9] [Reference Citation Analysis (0)] |
25. | Oura K, Morishita A, Tani J, Masaki T. Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review. Int J Mol Sci. 2021;22. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 40] [Cited by in F6Publishing: 188] [Article Influence: 62.7] [Reference Citation Analysis (0)] |
26. | Kurebayashi Y, Ojima H, Tsujikawa H, Kubota N, Maehara J, Abe Y, Kitago M, Shinoda M, Kitagawa Y, Sakamoto M. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology. 2018;68:1025-1041. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 216] [Cited by in F6Publishing: 308] [Article Influence: 51.3] [Reference Citation Analysis (0)] |
27. | Zhang QF, Yin WW, Xia Y, Yi YY, He QF, Wang X, Ren H, Zhang DZ. Liver-infiltrating CD11b-CD27- NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression. Cell Mol Immunol. 2017;14:819-829. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 87] [Cited by in F6Publishing: 104] [Article Influence: 13.0] [Reference Citation Analysis (0)] |
28. | 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;59:1415-1426. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 224] [Cited by in F6Publishing: 274] [Article Influence: 27.4] [Reference Citation Analysis (0)] |
29. | Ji J, Eggert T, Budhu A, Forgues M, Takai A, Dang H, Ye Q, Lee JS, Kim JH, Greten TF, Wang XW. Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology. 2015;62:481-495. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 103] [Cited by in F6Publishing: 108] [Article Influence: 12.0] [Reference Citation Analysis (0)] |
30. | Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 2009;69:8067-8075. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 245] [Cited by in F6Publishing: 286] [Article Influence: 19.1] [Reference Citation Analysis (0)] |
31. | Zhou J, Ding T, Pan W, Zhu LY, Li L, Zheng L. Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer. 2009;125:1640-1648. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 180] [Cited by in F6Publishing: 193] [Article Influence: 12.9] [Reference Citation Analysis (0)] |
32. | Sharma S, Khosla R, David P, Rastogi A, Vyas A, Singh D, Bhardwaj A, Sahney A, Maiwall R, Sarin SK, Trehanpati N. CD4+CD25+CD127(low) Regulatory T Cells Play Predominant Anti-Tumor Suppressive Role in Hepatitis B Virus-Associated Hepatocellular Carcinoma. Front Immunol. 2015;6:49. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 17] [Cited by in F6Publishing: 21] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
33. | Neureiter D, Stintzing S, Kiesslich T, Ocker M. Hepatocellular carcinoma: Therapeutic advances in signaling, epigenetic and immune targets. World J Gastroenterol. 2019;25:3136-3150. [PubMed] [DOI] [Cited in This Article: ] [Cited by in CrossRef: 42] [Cited by in F6Publishing: 44] [Article Influence: 8.8] [Reference Citation Analysis (0)] |
34. | Zhang F, Wang H, Wang X, Jiang G, Liu H, Zhang G, Fang R, Bu X, Cai S, Du J. TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget. 2016;7:52294-52306. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 213] [Cited by in F6Publishing: 335] [Article Influence: 55.8] [Reference Citation Analysis (0)] |
35. | Ahmadzadeh M, Rosenberg SA. TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol. 2005;174:5215-5223. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 144] [Cited by in F6Publishing: 162] [Article Influence: 8.5] [Reference Citation Analysis (0)] |
36. | Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol. 2001;166:7282-7289. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 402] [Cited by in F6Publishing: 415] [Article Influence: 18.0] [Reference Citation Analysis (0)] |
37. | Peng L, Yuan XQ, Zhang CY, Ye F, Zhou HF, Li WL, Liu ZY, Zhang YQ, Pan X, Li GC. High TGF-β1 expression predicts poor disease prognosis in hepatocellular carcinoma patients. Oncotarget. 2017;8:34387-34397. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 35] [Article Influence: 5.8] [Reference Citation Analysis (0)] |
38. | Feun LG, Li YY, Wu C, Wangpaichitr M, Jones PD, Richman SP, Madrazo B, Kwon D, Garcia-Buitrago M, Martin P, Hosein PJ, Savaraj N. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Cancer. 2019;125:3603-3614. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 75] [Cited by in F6Publishing: 124] [Article Influence: 24.8] [Reference Citation Analysis (0)] |
39. | Xu W, Liu K, Chen M, Sun JY, McCaughan GW, Lu XJ, Ji J. Immunotherapy for hepatocellular carcinoma: recent advances and future perspectives. Ther Adv Med Oncol. 2019;11:1758835919862692. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 63] [Cited by in F6Publishing: 72] [Article Influence: 14.4] [Reference Citation Analysis (0)] |
40. | Stewart CA, Metheny H, Iida N, Smith L, Hanson M, Steinhagen F, Leighty RM, Roers A, Karp CL, Müller W, Trinchieri G. Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation. J Clin Invest. 2013;123:4859-4874. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 130] [Cited by in F6Publishing: 129] [Article Influence: 11.7] [Reference Citation Analysis (0)] |
41. | Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 2009;206:1327-1337. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 591] [Cited by in F6Publishing: 698] [Article Influence: 46.5] [Reference Citation Analysis (0)] |
42. | Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T, Nakamoto Y, Kaneko S. Increase in CD14+HLA-DR -/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol Immunother. 2013;62:1421-1430. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 205] [Cited by in F6Publishing: 199] [Article Influence: 18.1] [Reference Citation Analysis (0)] |
43. | Lee IC, Huang YH, Chau GY, Huo TI, Su CW, Wu JC, Lin HC. Serum interferon gamma level predicts recurrence in hepatocellular carcinoma patients after curative treatments. Int J Cancer. 2013;133:2895-2902. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 8] [Cited by in F6Publishing: 21] [Article Influence: 1.9] [Reference Citation Analysis (0)] |
44. | Chen KJ, Lin SZ, Zhou L, Xie HY, Zhou WH, Taki-Eldin A, Zheng SS. Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS One. 2011;6:e24671. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 147] [Cited by in F6Publishing: 176] [Article Influence: 13.5] [Reference Citation Analysis (0)] |
45. | Yeung OW, Lo CM, Ling CC, Qi X, Geng W, Li CX, Ng KT, Forbes SJ, Guan XY, Poon RT, Fan ST, Man K. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J Hepatol. 2015;62:607-616. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 288] [Cited by in F6Publishing: 288] [Article Influence: 32.0] [Reference Citation Analysis (0)] |
46. | Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586-2593. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 787] [Cited by in F6Publishing: 859] [Article Influence: 50.5] [Reference Citation Analysis (0)] |
47. | Zhou SL, Zhou ZJ, Hu ZQ, Huang XW, Wang Z, Chen EB, Fan J, Cao Y, Dai Z, Zhou J. Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. Gastroenterology. 2016;150:1646-1658.e17. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 399] [Cited by in F6Publishing: 544] [Article Influence: 68.0] [Reference Citation Analysis (0)] |
48. | Affo S, Yu LX, Schwabe RF. The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer. Annu Rev Pathol. 2017;12:153-186. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 263] [Cited by in F6Publishing: 429] [Article Influence: 53.6] [Reference Citation Analysis (0)] |
49. | Apte RS, Chen DS, Ferrara N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019;176:1248-1264. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 742] [Cited by in F6Publishing: 1464] [Article Influence: 366.0] [Reference Citation Analysis (0)] |
50. | Courau T, Nehar-Belaid D, Florez L, Levacher B, Vazquez T, Brimaud F, Bellier B, Klatzmann D. TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies. JCI Insight. 2016;1:e85974. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 64] [Cited by in F6Publishing: 89] [Article Influence: 11.1] [Reference Citation Analysis (0)] |
51. | Webb ES, Liu P, Baleeiro R, Lemoine NR, Yuan M, Wang YH. Immune checkpoint inhibitors in cancer therapy. J Biomed Res. 2018;32:317-326. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 90] [Cited by in F6Publishing: 63] [Article Influence: 10.5] [Reference Citation Analysis (0)] |
52. | Greten TF, Sangro B. Targets for immunotherapy of liver cancer. J Hepatol. 2017;. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 104] [Cited by in F6Publishing: 104] [Article Influence: 14.9] [Reference Citation Analysis (0)] |
53. | El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, 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, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492-2502. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2536] [Cited by in F6Publishing: 3039] [Article Influence: 434.1] [Reference Citation Analysis (1)] |
54. | Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, Kudo M, Harding JJ, Merle P, Rosmorduc O, Wyrwicz L, Schott E, Choo SP, Kelley RK, Sieghart W, Assenat E, Zaucha R, Furuse J, Abou-Alfa GK, El-Khoueiry AB, Melero I, Begic D, Chen G, Neely J, Wisniewski T, Tschaika M, Sangro B. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23:77-90. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 104] [Cited by in F6Publishing: 552] [Article Influence: 184.0] [Reference Citation Analysis (0)] |
55. | 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;19:940-952. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1184] [Cited by in F6Publishing: 1692] [Article Influence: 282.0] [Reference Citation Analysis (0)] |
56. | Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, Okusaka T, Kobayashi M, Kumada H, Kaneko S, Pracht M, Mamontov K, Meyer T, Kubota T, Dutcus CE, Saito K, Siegel AB, Dubrovsky L, Mody K, Llovet JM. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020;38:2960-2970. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 661] [Cited by in F6Publishing: 721] [Article Influence: 180.3] [Reference Citation Analysis (0)] |
57. | Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382:1894-1905. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2542] [Cited by in F6Publishing: 3800] [Article Influence: 950.0] [Reference Citation Analysis (1)] |
58. | Tagliamonte M, Petrizzo A, Mauriello A, Tornesello ML, Buonaguro FM, Buonaguro L. Potentiating cancer vaccine efficacy in liver cancer. Oncoimmunology. 2018;7:e1488564. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 22] [Cited by in F6Publishing: 26] [Article Influence: 4.3] [Reference Citation Analysis (0)] |
59. | Repáraz D, Aparicio B, Llopiz D, Hervás-Stubbs S, Sarobe P. Therapeutic Vaccines against Hepatocellular Carcinoma in the Immune Checkpoint Inhibitor Era: Time for Neoantigens? Int J Mol Sci. 2022;23. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 4] [Cited by in F6Publishing: 4] [Article Influence: 2.0] [Reference Citation Analysis (0)] |
60. | Buonaguro L; HEPAVAC Consortium. Developments in cancer vaccines for hepatocellular carcinoma. Cancer Immunol Immunother. 2016;65:93-99. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 51] [Cited by in F6Publishing: 36] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
61. | Johnson PJ. Role of alpha-fetoprotein in the diagnosis and management of hepatocellular carcinoma. J Gastroenterol Hepatol. 1999;14 Suppl:S32-S36. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 72] [Cited by in F6Publishing: 70] [Article Influence: 2.8] [Reference Citation Analysis (0)] |
62. | Herrero A, Boivineau L, Cassese G, Assenat E, Riviere B, Faure S, Bedoya JU, Panaro F, Guiu B, Navarro F, Pageaux GP. Progression of AFP SCORE is a Preoperative Predictive Factor of Microvascular Invasion in Selected Patients Meeting Liver Transplantation Criteria for Hepatocellular Carcinoma. Transpl Int. 2022;35:10412. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 7] [Reference Citation Analysis (0)] |
63. | Butterfield LH, Koh A, Meng W, Vollmer CM, Ribas A, Dissette V, Lee E, Glaspy JA, McBride WH, Economou JS. Generation of human T-cell responses to an HLA-A2.1-restricted peptide epitope derived from alpha-fetoprotein. Cancer Res. 1999;59:3134-3142. [PubMed] [Cited in This Article: ] |
64. | Butterfield LH, Economou JS, Gamblin TC, Geller DA. Alpha fetoprotein DNA prime and adenovirus boost immunization of two hepatocellular cancer patients. J Transl Med. 2014;12:86. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 35] [Cited by in F6Publishing: 39] [Article Influence: 3.9] [Reference Citation Analysis (0)] |
65. | Mizukoshi E, Honda M, Arai K, Yamashita T, Nakamoto Y, Kaneko S. Expression of multidrug resistance-associated protein 3 and cytotoxic T cell responses in patients with hepatocellular carcinoma. J Hepatol. 2008;49:946-954. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in F6Publishing: 24] [Article Influence: 1.5] [Reference Citation Analysis (0)] |
66. | Tomonari T, Takeishi S, Taniguchi T, Tanaka T, Tanaka H, Fujimoto S, Kimura T, Okamoto K, Miyamoto H, Muguruma N, Takayama T. MRP3 as a novel resistance factor for sorafenib in hepatocellular carcinoma. Oncotarget. 2016;7:7207-7215. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in F6Publishing: 44] [Article Influence: 5.5] [Reference Citation Analysis (0)] |
67. | Mizukoshi E, Nakagawa H, Kitahara M, Yamashita T, Arai K, Sunagozaka H, Iida N, Fushimi K, Kaneko S. Phase I trial of multidrug resistance-associated protein 3-derived peptide in patients with hepatocellular carcinoma. Cancer Lett. 2015;369:242-249. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 28] [Cited by in F6Publishing: 31] [Article Influence: 3.4] [Reference Citation Analysis (0)] |
68. | Yamashita T, Arai K, Sunagozaka H, Ueda T, Terashima T, Yamashita T, Mizukoshi E, Sakai A, Nakamoto Y, Honda M, Kaneko S. Randomized, phase II study comparing interferon combined with hepatic arterial infusion of fluorouracil plus cisplatin and fluorouracil alone in patients with advanced hepatocellular carcinoma. Oncology. 2011;81:281-290. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 53] [Cited by in F6Publishing: 59] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
69. | Nishida T, Kataoka H. Glypican 3-Targeted Therapy in Hepatocellular Carcinoma. Cancers (Basel). 2019;11. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 81] [Cited by in F6Publishing: 79] [Article Influence: 15.8] [Reference Citation Analysis (0)] |
70. | Sawada Y, Yoshikawa T, Nobuoka D, Shirakawa H, Kuronuma T, Motomura Y, Mizuno S, Ishii H, Nakachi K, Konishi M, Nakagohri T, Takahashi S, Gotohda N, Takayama T, Yamao K, Uesaka K, Furuse J, Kinoshita T, Nakatsura T. Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res. 2012;18:3686-3696. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 201] [Cited by in F6Publishing: 208] [Article Influence: 17.3] [Reference Citation Analysis (0)] |
71. | Sawada Y, Yoshikawa T, Ofuji K, Yoshimura M, Tsuchiya N, Takahashi M, Nobuoka D, Gotohda N, Takahashi S, Kato Y, Konishi M, Kinoshita T, Ikeda M, Nakachi K, Yamazaki N, Mizuno S, Takayama T, Yamao K, Uesaka K, Furuse J, Endo I, Nakatsura T. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunology. 2016;5:e1129483. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 97] [Cited by in F6Publishing: 115] [Article Influence: 14.4] [Reference Citation Analysis (0)] |
72. | Kirn D, Martuza RL, Zwiebel J. Replication-selective virotherapy for cancer: Biological principles, risk management and future directions. Nat Med. 2001;7:781-787. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 393] [Cited by in F6Publishing: 375] [Article Influence: 16.3] [Reference Citation Analysis (0)] |
73. | Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, Cho M, Lim HY, Chung HC, Kim CW, Burke J, Lencioni R, Hickman T, Moon A, Lee YS, Kim MK, Daneshmand M, Dubois K, Longpre L, Ngo M, Rooney C, Bell JC, Rhee BG, Patt R, Hwang TH, Kirn DH. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19:329-336. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 490] [Cited by in F6Publishing: 577] [Article Influence: 52.5] [Reference Citation Analysis (0)] |
74. | Moehler M, Heo J, Lee HC, Tak WY, Chao Y, Paik SW, Yim HJ, Byun KS, Baron A, Ungerechts G, Jonker D, Ruo L, Cho M, Kaubisch A, Wege H, Merle P, Ebert O, Habersetzer F, Blanc JF, Rosmorduc O, Lencioni R, Patt R, Leen AM, Foerster F, Homerin M, Stojkowitz N, Lusky M, Limacher JM, Hennequi M, Gaspar N, McFadden B, De Silva N, Shen D, Pelusio A, Kirn DH, Breitbach CJ, Burke JM. Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE). Oncoimmunology. 2019;8:1615817. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 54] [Cited by in F6Publishing: 84] [Article Influence: 16.8] [Reference Citation Analysis (0)] |
75. | Wang Q, Luan W, Warren L, Kadri H, Kim KW, Goz V, Blank S, Isabel Fiel M, Hiotis SP. Autologous Tumor Cell Lysate-Loaded Dendritic Cell Vaccine Inhibited Tumor Progression in an Orthotopic Murine Model for Hepatocellular Carcinoma. Ann Surg Oncol. 2016;23:574-582. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 9] [Cited by in F6Publishing: 10] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
76. | Iwashita Y, Tahara K, Goto S, Sasaki A, Kai S, Seike M, Chen CL, Kawano K, Kitano S. A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer. Cancer Immunol Immunother. 2003;52:155-161. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 91] [Cited by in F6Publishing: 96] [Article Influence: 4.6] [Reference Citation Analysis (0)] |
77. | Mizukoshi E, Nakamoto Y, Arai K, Yamashita T, Mukaida N, Matsushima K, Matsui O, Kaneko S. Enhancement of tumor-specific T-cell responses by transcatheter arterial embolization with dendritic cell infusion for hepatocellular carcinoma. Int J Cancer. 2010;126:2164-2174. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 10] [Cited by in F6Publishing: 22] [Article Influence: 1.6] [Reference Citation Analysis (0)] |
78. | Kerkar SP, Wang ZF, Lasota J, Park T, Patel K, Groh E, Rosenberg SA, Miettinen MM. MAGE-A is More Highly Expressed Than NY-ESO-1 in a Systematic Immunohistochemical Analysis of 3668 Cases. J Immunother. 2016;39:181-187. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in F6Publishing: 49] [Article Influence: 6.1] [Reference Citation Analysis (0)] |
79. | Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62-68. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1753] [Cited by in F6Publishing: 1712] [Article Influence: 190.2] [Reference Citation Analysis (0)] |
80. | Wang P, Qin W, Liu T, Jiang D, Cui L, Liu X, Fang Y, Tang X, Jin H, Qian Q. PiggyBac-engineered T cells expressing a glypican-3-specific chimeric antigen receptor show potent activities against hepatocellular carcinoma. Immunobiology. 2020;225:151850. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 20] [Cited by in F6Publishing: 21] [Article Influence: 4.2] [Reference Citation Analysis (0)] |
81. | Wu X, Luo H, Shi B, Di S, Sun R, Su J, Liu Y, Li H, Jiang H, Li Z. Combined Antitumor Effects of Sorafenib and GPC3-CAR T Cells in Mouse Models of Hepatocellular Carcinoma. Mol Ther. 2019;27:1483-1494. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 65] [Cited by in F6Publishing: 102] [Article Influence: 20.4] [Reference Citation Analysis (0)] |
82. | 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;356:802-807. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 630] [Cited by in F6Publishing: 634] [Article Influence: 26.4] [Reference Citation Analysis (0)] |
83. | 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;41:36-41. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 110] [Cited by in F6Publishing: 122] [Article Influence: 8.1] [Reference Citation Analysis (0)] |
84. | Yoon JS, Song BG, Lee JH, Lee HY, Kim SW, Chang Y, Lee YB, Cho EJ, Yu SJ, Sinn DH, Kim YJ, Yoon JH. Adjuvant cytokine-induced killer cell immunotherapy for hepatocellular carcinoma: a propensity score-matched analysis of real-world data. BMC Cancer. 2019;19:523. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 11] [Cited by in F6Publishing: 14] [Article Influence: 2.8] [Reference Citation Analysis (0)] |
85. | Huang ZM, Li W, Li S, Gao F, Zhou QM, Wu FM, He N, Pan CC, Xia JC, Wu PH, Zhao M. Cytokine-induced killer cells in combination with transcatheter arterial chemoembolization and radiofrequency ablation for hepatocellular carcinoma patients. J Immunother. 2013;36:287-293. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 47] [Cited by in F6Publishing: 54] [Article Influence: 4.9] [Reference Citation Analysis (0)] |
86. | 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;148:1383-91.e6. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 283] [Cited by in F6Publishing: 360] [Article Influence: 40.0] [Reference Citation Analysis (0)] |
87. | 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;6:41339-41349. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 54] [Cited by in F6Publishing: 61] [Article Influence: 7.6] [Reference Citation Analysis (0)] |
88. | Aznar MA, Tinari N, Rullán AJ, Sánchez-Paulete AR, Rodriguez-Ruiz ME, Melero I. Intratumoral Delivery of Immunotherapy-Act Locally, Think Globally. J Immunol. 2017;198:31-39. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 131] [Cited by in F6Publishing: 148] [Article Influence: 21.1] [Reference Citation Analysis (0)] |
89. | Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, Kagaya T, Fushimi K, Kaneko S. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology. 2013;57:1448-1457. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 147] [Cited by in F6Publishing: 186] [Article Influence: 16.9] [Reference Citation Analysis (0)] |
90. | Rodríguez-Ruiz ME, Perez-Gracia JL, Rodríguez I, Alfaro C, Oñate C, Pérez G, Gil-Bazo I, Benito A, Inogés S, López-Diaz de Cerio A, Ponz-Sarvise M, Resano L, Berraondo P, Barbés B, Martin-Algarra S, Gúrpide A, Sanmamed MF, de Andrea C, Salazar AM, Melero I. Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients. Ann Oncol. 2018;29:1312-1319. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 75] [Cited by in F6Publishing: 80] [Article Influence: 13.3] [Reference Citation Analysis (0)] |
91. | Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, Davis JL, Hughes MS, Heller T, ElGindi M, Uppala A, Korangy F, Kleiner DE, Figg WD, Venzon D, Steinberg SM, Venkatesan AM, Krishnasamy V, Abi-Jaoudeh N, Levy E, Wood BJ, Greten TF. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017;66:545-551. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 454] [Cited by in F6Publishing: 581] [Article Influence: 83.0] [Reference Citation Analysis (0)] |
92. | Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, Ruth He A, El-Rayes BF, Acosta-Rivera M, Lim HY, Neely J, Shen Y, Wisniewski T, Anderson J, Hsu C. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020;6:e204564. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 505] [Cited by in F6Publishing: 789] [Article Influence: 197.3] [Reference Citation Analysis (0)] |
93. | Shimizu K, Kotera Y, Aruga A, Takeshita N, Katagiri S, Ariizumi S, Takahashi Y, Yoshitoshi K, Takasaki K, Yamamoto M. Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma. Hum Vaccin Immunother. 2014;10:970-976. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in F6Publishing: 40] [Article Influence: 4.0] [Reference Citation Analysis (1)] |
94. | Harding JJ, Nandakumar S, Armenia J, Khalil DN, Albano M, Ly M, Shia J, Hechtman JF, Kundra R, El Dika I, Do RK, Sun Y, Kingham TP, D'Angelica MI, Berger MF, Hyman DM, Jarnagin W, Klimstra DS, Janjigian YY, Solit DB, Schultz N, Abou-Alfa GK. Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next-Generation Sequencing for Matching Patients to Targeted and Immune Therapies. Clin Cancer Res. 2019;25:2116-2126. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 254] [Cited by in F6Publishing: 379] [Article Influence: 63.2] [Reference Citation Analysis (0)] |