• Chimeric antigen receptor cells
• Hepatocellular carcinoma
• T lymphocyte
• Tumor-infiltrating lymphocytes

• BiTE
• CAR-T cell therapy
• cancer immunotherapy
• cancer vaccine
• glypican-3

• Glypicans/immunology
• Humans
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/therapy
• Liver Neoplasms/immunology
• Liver Neoplasms/drug therapy
• Animals
• Immunotherapy/methods
• Cancer Vaccines/administration & dosage
• Cancer Vaccines/immunology
• Antigens, Neoplasm/immunology
• Molecular Targeted Therapy

• CD8+ T Cell Dynamics
• HBV‐Associated Liver Diseases
• Review

• Humans
• CD8-Positive T-Lymphocytes/immunology
• Hepatitis B virus/pathogenicity
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/therapy
• Hepatitis B, Chronic/complications
• Hepatitis B, Chronic/drug therapy
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/immunology
• Liver Neoplasms/therapy
• Liver Neoplasms/immunology
• Liver Neoplasms/virology
• Liver Diseases/immunology
• Liver Diseases/therapy
• Liver Diseases/virology

• 32270950 National Natural Science Foundation of China
• 32030036 National Natural Science Foundation of China
• 82002787 National Natural Science Foundation of China
• 82230067 National Natural Science Foundation of China
• 2414050004764 Natural Science Foundation of Guangdong Province of China
• YNXM20210305 Startup Foundation of the Zhuhai People's Hospital
• National Natural Science Foundation of China

Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality, and is prone to intra- and extrahepatic metastasis due to the anatomical and functional characteristics of the liver. Due to the complexity and high relapse rate associated with radical surgery or radiofrequency ablation, immune checkpoint inhibitors (ICIs) are increasingly being used to treat HCC. Several immunotherapeutic agents, along with their combinations, have been clinically approved to treat advanced or recurrent HCC. This review discusses the leading ICIs in practice and those currently undergoing randomized phase 1–3 trials as monotherapy or combination therapy. Furthermore, we summarize the rapidly developing alternative strategies such as chimeric antigen receptor-engineered T cell therapy and tumor vaccines. Combination therapy is a promising potential treatment option. These immunotherapies are also summarized in this review, which provides insights into the advantages, limitations, and novel angles for future research in establishing viable and alternative therapies against HCC.

• Recurrent hepatocellular carcinoma
• Immunotherapy
• Immune checkpoint inhibitor
• Chimeric antigen receptor-engineered T cell
• Oncolytic virus
• Tumor vaccine

• CAR T-cell
• challenges
• chimeric antigen receptor
• clinical trials
• immunotherapy
• solid tumors

• Student Research Committee, Tabriz University of Medical Sciences

• drug delivery
• glypican 3
• hepatocellular carcinoma
• nanomedicine
• polymeric nanoparticles
• targeted therapy

• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Drug Resistance
• Glypicans/metabolism
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Nanotechnology
• Therapies, Investigational

• NA Governo Italiano

• Animals
• Carcinoma, Hepatocellular
• Glypicans
• Liver Neoplasms
• Lung Neoplasms
• Male
• Mice
• Receptors, Chimeric Antigen
• Sorafenib/therapeutic use
• T-Lymphocytes
• Xenograft Model Antitumor Assays

• CART cells
• Immunosenescence
• bispecific T-cell engagers
• immune checkpoint inhibitors
• inflammaging
• older patients

• CD8(+) T lymphocytes
• Cytotoxicity
• Dysfunction
• Hepatocellular carcinoma
• Natural Killer cells

Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC.

• CTL
• NK cell
• hepatocellular carcinoma
• immunotherapy
• viral hepatitis

The cytotoxic T cell response against hepatocellular carcinoma antigens is exhausted and fails in its task of deleting tumoral cells. These cells are featured by the expression of negative immune checkpoints that can be modulated to restore T cell function. The blockade of the PD-1/PD-L1 pathway has shown promising results in rescuing hepatocellular carcinoma-specific CD8 T cells but only a reduced group of cases is sensitive to this treatment and the effect is usually temporary. Therefore, new anti-PD-1 based combinatory strategies are underway to increase the response by adding the effect of blocking neo-angiogenesis and other negative immune checkpoints, boosting positive immune checkpoints, blocking suppressive cytokines, or inducing the expression of tumoral neoantigens. The restoration of T cell responses with these anti-PD-1 based combinatory therapies will change the outcome of advanced hepatocellular carcinoma.

Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8⁺ T cells is discussed in this review.

• CD8 T cell response
• PD-1
• PD-L1
• combination therapy
• hepatocellular carcinoma
• immune check-point inhibitor
• immunotherapy

Chimeric antigen receptor T (CAR-T) cell therapy utilizes patients' own T lymphocytes that are engineered to attack cancer cells. It is Food and Drug Administration (FDA)-approved in various hematological malignancies and currently being evaluated in solid cancers in early phase studies. We did a systematic review consisting of 15 prospective clinical trials (n=159) evaluating CAR-T cells in solid cancers. Early phase trials showed promising response rates in ovarian epithelial cancer (100%), human epidermal growth factor receptor 2 (HER2)-positive sarcoma (67%), epidermal growth factor receptor (EGFR)-positive biliary tract cancer (65%), advanced gastric/pancreatic cancer (82%), hepatocellular carcinoma (67%), and colorectal cancer (70%). The median overall response across all malignancies was 62% (range 17%-100%). Median progression-free survival and overall survival were not reached in most trials. Cytokine release syndrome was seen in only one patient with cholangiocarcinoma who received EGFR-specific CAR-T cell therapy. Although survival data is still not mature, CAR-T cell therapy in solid malignancies did show encouraging response rates and was well-tolerated.

• car-t
• chimeric antigen receptor (car) t-cell
• solid tumor

• CAR-T
• clinical trials
• digestive system cancers
• solid tumors

• HCC
• immunotherapy
• innate immunity
• tumor microenvironment

• Animals
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Humans
• Immunity, Innate
• Immunotherapy/methods
• Liver Neoplasms/immunology
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Lymphocytes, Tumor-Infiltrating/immunology

• ZIA BC011345 Intramural NIH HHS
• U.S. Department of Health & Human Services | National Institutes of Health (NIH)

• Combination therapy
• Epigenetic drugs
• Gut microbiota
• Hepatocellular carcinoma (HCC)
• Immunotherapy

• Checkpoint inhibitor
• Hepatocellular carcinoma
• Immunotherapy

• Adoptive T cell therapy
• CAR-T cell therapy
• Checkpoint inhibitor
• Cytokine-induced killer cells
• Hepatocellular carcinoma
• TCR T cells
• Tumor-infiltrating lymphocytes

Certain immune cells, namely T cells, of cancer patients can be genetically manipulated to express so-called chimeric antigen receptors (CARs), which enables these cells to kill the tumor cells after recognition by the receptor. This therapy is very successful in the treatment of hematologic tumors such as lymphoma or leukemia. However, tumors growing as a solid mass are less susceptible to this kind of treatment. This review summarizes known data of all clinical trials using this therapy against solid tumors that are registered at clinicaltrials.gov.

CAR-T cells showed great potential in the treatment of patients with hematologic tumors. However, the clinical efficacy of CAR-T cells against solid tumors lags behind. To obtain a comprehensive overview of the landscape of CAR-T cell clinical trials against this type of cancer, this review summarizes all the 196 studies registered at clinicaltrials.gov. Special focus is on: (1) geographical distribution; (2) targeted organs, tumor entities, and antigens; (3) CAR transfer methods, CAR formats, and extra features introduced into the T cells; and (4) patient pretreatments, injection sites, and safety measurements. Finally, the few data on clinical outcome are reported. The last assessment of clinicaltrials.gov for the data summarized in this paper was on 4 August 2020.

• CAR format
• CAR transfer
• CAR-T cell
• clinical trial
• clinicaltrials.gov
• solid tumor
• suicide switch
• tumor antigen

Treatment of hepatocellular carcinoma (HCC) using antibody-based targeted therapies, such as antibody conjugates and chimeric antigen receptor T (CAR-T) cell therapy, shows potent antitumor efficacy. Glypican-3 (GPC3) is an emerging HCC therapeutic target; therefore, antibodies against GPC3 would be useful tools for developing immunotherapies for HCC.

We isolated a novel human monoclonal antibody, 32A9, by phage display technology. We determined specificity, affinity, epitope and anti-tumor activity of 32A9, and developed 32A9-based immunotherapy technologies for evaluating the potency of HCC treatment in vitro or in vivo.

32A9 recognized human GPC3 with potent affinity and specificity. The epitope of 32A9 was located in the region of the GPC3 protein core close to the modification sites of the HS chain and outside of the Wnt-binding site of GPC3. The 32A9 antibody significantly inhibited HCC xenograft tumor growth in vivo. We then pursued two 32A9-based immunotherapeutic strategies by constructing an immunotoxin and CAR-T cells. The 32A9 immunotoxin exhibited specific cytotoxicity to GPC3-positive cancer cells, while 32A9 CAR-T cells efficiently eliminated GPC3-positive HCC cells in vitro and caused HCC xenograft tumor regressions in vivo.

Our study provides a rationale for 32A9 as a promising GPC3-specific antibody candidate for HCC immunotherapy.

• Antibody
• Chimeric antigen receptor
• Glypican-3
• Immunotoxin
• Liver cancer

• CAR-T
• Chinese experience
• cell-based therapy
• clinical trial
• efficacy
• hematological malignancy
• novel strategy
• solid tumor
• toxicity

• Hepatic
• Immunotherapy
• Lymphocyte
• Tumor-Specific T Cells

• Aged
• Aged, 80 and over
• Animals
• Apoptosis
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Glypicans/genetics
• Glypicans/immunology
• Glypicans/metabolism
• Granzymes/metabolism
• Hep G2 Cells
• Humans
• Immunotherapy, Adoptive
• Liver Neoplasms/immunology
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Male
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Perforin/metabolism
• Receptors, Chimeric Antigen/genetics
• Receptors, Chimeric Antigen/immunology
• Receptors, Chimeric Antigen/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism
• T-Lymphocytes/transplantation
• Tumor Burden
• Tumor Microenvironment
• Wnt Signaling Pathway
• Xenograft Model Antitumor Assays

• HHSN261200800001C NCI NIH HHS
• UL1 TR000135 NCATS NIH HHS
• ZIA BC010891 Intramural NIH HHS
• Z01 BC010891 Intramural NIH HHS
• HHSN261200800001E NCI NIH HHS

• Adoptive cell therapy
• Biliary
• Checkpoint inhibition
• Colorectal
• Gastric
• Gastrointestinal cancer
• Hepatic
• Immunotherapy
• Oesophageal
• Pancreatic
• Review
• Vaccine

The use of allogeneic, pluripotent stem‐cell‐derived immune cells for cancer immunotherapy has been the subject of recent clinical trials. In Japan, investigator‐initiated clinical trials will soon begin for ovarian cancer treatment using human leukocyte antigen (HLA)‐homozygous‐induced pluripotent stem cell (iPSC)‐derived anti–glypican‐3 (GPC3) chimeric antigen receptor (CAR)‐expressing natural killer/innate lymphoid cells (NK/ILC). Using pluripotent stem cells as the source for allogeneic immune cells facilitates stringent quality control of the final product, in terms of efficacy, safety and producibility. In this paper, we describe our methods for the stable, feeder‐free production of CAR‐expressing NK/ILC cells from CAR‐transduced iPSC with clinically relevant scale and materials. The average number of cells that could be differentiated from 1.8‐3.6 × 10⁶ iPSC within 7 weeks was 1.8‐4.0 × 10⁹. These cells showed stable CD45/CD7/CAR expression, effector functions of cytotoxicity and interferon gamma (IFN‐γ) production against GPC3‐expressing tumor cells. When the CAR‐NK/ILC cells were injected into a GPC3‐positive, ovarian‐tumor‐bearing, immunodeficient mouse model, we observed a significant therapeutic effect that prolonged the survival of the animals. When the cells were injected into immunodeficient mice during non–clinical safety tests, no acute systemic toxicity or tumorigenicity of the final product or residual iPSC was observed. In addition, our test results for the CAR‐NK/ILC cells generated with clinical manufacturing standards are encouraging, and these methods should accelerate the development of allogeneic pluripotent stem cell‐based immune cell cancer therapies.

• GPC3
• ILC
• NK
• chimeric antigen receptor
• iPSC
• immunotherapy

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage.

• CTLA-4
• PD-1
• combination therapy
• hepatocellular carcinoma
• immune checkpoint inhibitor
• immunotherapy

• il15
• il21
• glypican-3
• car t cells
• hepatocellular carcinoma

• Animals
• Apoptosis/immunology
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Cell Proliferation/physiology
• Female
• Glypicans/genetics
• Glypicans/immunology
• Humans
• Immunotherapy, Adoptive/methods
• Interleukin-15/biosynthesis
• Interleukin-15/genetics
• Interleukin-15/immunology
• Interleukins/biosynthesis
• Interleukins/genetics
• Interleukins/immunology
• Liver Neoplasms/immunology
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

• R01 CA258866 NCI NIH HHS
• S10 OD020066 NIH HHS

Cell surface proteins act as the go-between in carrying the information from the extracellular environment to the intracellular signaling proteins. However, these proteins are often deregulated in neoplastic diseases, including hepatocellular carcinoma. This review discusses several recent studies that have investigated the role of cell surface proteins in the occurrence and progression of HCC, highlighting the possibility to use them as biomarkers of the disease and/or targets for vaccines and therapeutics.

• biomarker
• cell surface proteins
• clinical trial
• hepatocellular carcinoma
• therapeutic target

• Hepatocellular carcinoma
• clinical trials
• hepatitis C virus
• hepatitis B virus
• immunotherapy
• liver cancer
• targeted therapy

• Anilides/therapeutic use
• Antibodies, Monoclonal, Humanized/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Humans
• Immunotherapy
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Molecular Targeted Therapy
• Nivolumab/therapeutic use
• Phenylurea Compounds/therapeutic use
• Progression-Free Survival
• Pyridines/therapeutic use
• Ramucirumab

• biliary tract cancers
• checkpoint inhibitor
• drug combination
• hepatocellular carcinoma
• immunology
• tumor microenvironment

• P30 CA008748 NCI NIH HHS

• Cancer vaccine
• Checkpoint inhibitors
• Epigenetic drugs
• Immunotherapy
• Liver cancer

IL12 is an immune-stimulatory cytokine for key immune cells including T cells and NK cells. However, systemic administration of IL12 has serious side effects that limit its clinical application in patients. Recently, synthetic Notch (synNotch) receptors have been developed that induce transcriptional activation and deliver therapeutic payloads in response to the reorganization of specific antigens. NK92 cell is a human natural killer (NK) cell line which has been developed as tools for adjuvant immunotherapy of cancer. Here, we explored the possibility of using synNotch receptor-engineered NK92 cells to selectively secrete IL12 at the tumor site and increase the antitumor activities of chimeric antigen receptor (CAR)-modified T cells. Compared with the nuclear factor of activated T-cells (NFATs) responsive promoter, which is another regulatory element, the synNotch receptor was better at controlling the expression of cytokines. NK92 cells transduced with the GPC3-specific synNotch receptor could produce the proinflammatory cytokine IL12 (GPC3-Syn-IL12-NK92) in response to GPC3 antigen expressed in cancer cells. In vivo GPC3-Syn-IL12-NK92 cells controlling IL12 production could enhance the antitumor ability of GPC3-redirected CAR T cells and increase the infiltration of T cells without inducing toxicity. Taken together, our results demonstrated that IL12 supplementation by synNotch-engineered NK92 cells could secrete IL12 in a target-dependent manner, and promote the antitumor efficiency of CAR-T cells. Local expression of IL12 by synNotch-engineered NK92 cells might be a safe approach to enhance the clinical outcome of CAR-T cell therapy.

• CAR-T
• IL12
• NK92
• synNotch receptor
• toxicity

• Animals
• Cell- and Tissue-Based Therapy/adverse effects
• Cell- and Tissue-Based Therapy/methods
• Clinical Trials as Topic
• Humans
• Neoplasms/immunology
• Neoplasms/therapy
• Receptors, Chimeric Antigen/therapeutic use
• T-Lymphocytes/immunology
• T-Lymphocytes/transplantation
• Tumor Microenvironment/immunology

• P50 CA159981 NCI NIH HHS

• gastrointestinal cancer
• immune system
• immunotherapy
• predictive biomarker
• tumor microenvironment

• Animals
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/immunology
• Gastrointestinal Neoplasms/diagnosis
• Gastrointestinal Neoplasms/immunology
• Gastrointestinal Neoplasms/therapy
• Humans
• Immunity
• Immunotherapy/methods
• Prognosis
• Tumor Microenvironment

• MOST 106-3114-B-038-001, MOST 107-2321-B-038-002, MOST 107-2314-B-038-057, MOST 107-2314-B-038-061, MOST 108-2321-B-038-003, and MOST 107-2314-B-038-006 Ministry of Science and Technology, Taiwan
• MOHW107-TDU-B-212-114014, and MOHW108-TDU-B-212-124014) Health and Welfare Surcharge of Tobacco Products
• DP2-107-21121-01-T-02 and DP2-108-21121-01-T-02-02 Ministry of Education, Taiwan

• CAR-T
• T cell-redirecting antibody
• codrituzumab
• glypican-3
• hepatocellular carcinoma

• 16H05175 Japan Society for the Promotion of Science KAKENHI

• glypican-3
• hepatocellular carcinoma
• antibody-drug conjugate
• pyrrolobenzodiazepine
• combination therapy

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with dismal prognosis when diagnosed at advanced stages. Surgical resection of the primary tumor or orthotropic liver transplantation serves as a potential curative option. However, this approach is highly dependent on the hepatic reserve and baseline functional status of the patient. Liver directed therapies such as portal vein embolization (PVE), trans-arterial chemoembolization (TACE), and systemic chemotherapy are employed in non-surgical candidates. Sorafenib was the only approved systemic therapeutic agent for almost a decade until the recent approval of lenvatinib by the United States Food and Drug Administration (FDA) as an alternate first-line agent. Regorafenib, nivolumab, pembrolizumab and cabozantinib are approved by the FDA as second-line agents in patients who failed or could not tolerate sorafenib. Ramucirumab was recently FDA approved for the subset of patients that have high alfa-fetoprotein levels (>400 ng/mL). A better understanding of tumorigenesis and encouraging clinical trial results that evaluated immune-checkpoint inhibitors opened doors for immunotherapy in HCC. Immune checkpoint inhibitors have demonstrated a prolonged median overall and progression-free survival in a subset of patients with HCC. On-going translational and clinical research will hopefully provide us with a better understanding of tumor markers, genetic aberrations and other factors that determine the immunotherapy response in HCC. In this review, we sought to summarize the potential role and future directions of immunotherapy in the management of HCC.

• immunotherapy
• lenvatinib
• liver cancer
• nivolumab
• sorafenib

• Biomarker
• Checkpoint inhibitors
• Clinical trial
• Fibrosis
• Immunotherapy
• Liver cancer
• Mouse model
• Next-generation sequencing
• Non-alcoholic steatohepatitis
• Targeted therapy

• Animals
• Antineoplastic Agents, Immunological/pharmacology
• Antineoplastic Agents, Immunological/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/immunology
• Disease Models, Animal
• Drug Development
• Drug Discovery
• Epigenesis, Genetic/drug effects
• Histone Deacetylase Inhibitors/pharmacology
• Histone Deacetylase Inhibitors/therapeutic use
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/immunology
• Molecular Targeted Therapy/methods
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Signal Transduction/immunology
• Treatment Outcome

Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.

• Adoptive cell therapy
• Cancer vaccine
• Checkpoint inhibitor
• Hepatocellular carcinoma
• Immunotherapy
• Liver cancer
• Oncolytic virus

• Antineoplastic Agents, Immunological/therapeutic use
• Cancer Vaccines/therapeutic use
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/therapy
• Clinical Trials as Topic
• Combined Modality Therapy/methods
• Combined Modality Therapy/trends
• Humans
• Immunotherapy/methods
• Immunotherapy/trends
• Liver Neoplasms/immunology
• Liver Neoplasms/therapy
• Oncolytic Virotherapy/methods
• Oncolytic Virotherapy/trends
• Treatment Outcome

• GPC3
• chimeric antigen receptors
• hepatocellular carcinoma
• sorafenib
• tumor-associated macrophages

Chimeric antigen receptor modified T cells (CAR-T) therapy is an emerging immunotherapy against malignancies. However, only limited success was obtained in solid tumors. Polyinosinic-polycytidylic acid (poly I:C), ligand of TLR3, mediates innate immune and adaptive immune and shows broad antitumor effect on many types of cancer. In the present study, we combined EGFRvIII-targeted CAR-T cells with poly I:C treatment and evaluated the synergic antitumor effect in vitro and in immunocompetent mice bearing subcutaneous colon or orthotopic breast cancer xenografts. Poly I:C significantly promoted more IL-2 and IFN γ production as well as higher lytic activity of CAR-T cells. Upon systemic administration in vivo, CAR-T cells obviously suppressed tumor growth, and poly I:C significantly enhanced the suppression. Further study showed that poly I:C exerted antitumor effect dependent on type I IFNs. In addition, poly I:C decreased myeloid-derived suppressor cells (MDSC) number in peripheral blood and spleen, and attenuated the immunosuppressive activity of MDSC on proliferation and cytolytic function of CAR-T. Depletion of MDSC with anti-Gr1 Ab further increased the antitumor effect of CAR-T cells plus poly I:C treatment. In conclusion, CAR-T treatment combined with intratumoral delivery of poly I:C resulted in synergistic antitumor activity. We thus provide a rationale to translate this immunotherapeutic strategy to solid tumors.

• MDSC
• chimeric antigen receptor
• poly I:C
• solid tumor
• type I IFN

• CAR-T
• HCC
• Immunotherapy
• immune checkpoint inhibitors
• vaccination

• Adoptive cellular immunotherapy
• B7-H1 antigen
• CTLA-4 antigen
• Hepatocellular carcinoma
• Immunotherapy
• Programmed cell death 1 receptor

• Antineoplastic Agents/therapeutic use
• Cancer Vaccines
• Carcinoma, Hepatocellular/therapy
• Cell- and Tissue-Based Therapy
• Humans
• Immunotherapy
• Liver Neoplasms/therapy

Chimeric antigen receptor T (CAR-T) cell therapy has achieved unprecedented success among hematologic tumors, but its role in treating solid tumors is still unclear.

A comprehensive search of electronic databases up to June 1, 2018, was carried out by two independent reviewers. We included studies which focused on the association between CAR-T cell therapy and patient response rate and survival time in solid tumors.

22 studies with 262 patients were included in our meta-analysis. The overall pooled response rate of CAR-T cell therapy was 9% (95% confidence interval (CI): 4-16%). Subgroup analysis (analyses) demonstrated that CAR-T therapy could perform its best therapeutic effect on neuroblastoma, while barely works among gastrointestinal malignancies. Moreover, the treatment efficacy was not significantly impacted by different treatment strategies (lymphodepletion before T cell infusion, transfection method, cell culture duration, persistence of CAR-T cells, transfection efficacy, total cell dose, and administration of IL-2). Only T cell culture duration was associated with better clinical prognosis.

Although CAR-T cell therapy did not have satisfactory responses in solid tumors, researchers were still holding an optimistic attitude towards its future efficacy with more modifications of its structure.

Chimeric antigen receptor T cells (CAR T Cells) have led to dramatic improvements in the survival of cancer patients, most notably those with hematologic malignancies. Early phase clinical trials in patients with solid tumors have demonstrated them to be feasible, but unfortunately has yielded limited efficacy for various cancer types. In this article we will review the background on CAR T cells for the treatment of solid tumors, focusing on the unique obstacles that solid tumors present for the development of adoptive T cell therapy, and the novel approaches currently under development to overcome these hurdles.

• CAR T cells
• novel approaches
• solid tumors

• R01 CA136934 NCI NIH HHS
• R01 CA193167 NCI NIH HHS
• R01-CA136934 NIH HHS
• R01-CA193167 NIH HHS