Immunotherapeutic approaches in Hepatocellular carcinoma: Building blocks of hope in near future

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic cancer and is among the major causes of mortality due to cancer. Due to the lack of efficient conventional therapeutic options for this cancer, particularly in advanced cases, novel treatments including immunotherapy have been considered. However, despite the encouraging clinical outcomes after implementing these innovative approaches, such as oncolytic viruses (OVs), adoptive cell therapies (ACT), immune checkpoint blockades (ICBs), and cancer vaccines, several factors have restricted their therapeutic effect. The main concern is the existence of an immunosuppressive tumor microenvironment (TME). Combination of different ICBs or ICBs plus tyrosine kinase inhibitors have shown promising results in overcoming these limiting factors to some extent. Combination of programmed cell death ligand-1 (PD-L1) antibody Atezolizumab and vascular endothelial growth factor (VEGF) antibody Bevacizumab has become the standard of care in the first-line therapy for untestable HCC, approved by regulatory agencies. This paper highlighted a wide overview of the direct and indirect immunotherapeutic strategies proposed for the treatment of HCC patients and the common challenges that have hindered their further clinical applications.     

Immune microenvironment and therapeutic progress of recurrent hepatocellular carcinoma after liver transplantation

HCC is a highly lethal tumor, and orthotopic liver transplantation, as one of the radical treatment methods for HCC, has opened-up a new therapeutic approach for the treatment of primary liver cancer. However, tumor recurrence after liver transplantation is the main reason that affects the long-term survival of recipients. At present, the application of ICIs has brought dawn to patients with refractory HCC. However, because of the special immune tolerance state created by long-term oral immunosuppressants in patients with HCC after liver transplantation, the current focus is how to regulate the immune balance of such patients and simultaneously maximize the anti-tumor effect. This article reviews the relationship between liver cancer and immunity, immune tolerance of liver transplantation, immune microenvironment after liver transplantation for HCC, and the application of immunotherapy in the recurrence of liver transplantation for HCC.     

Cell- and peptide-based immunotherapeutic approaches for glioma

Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. Although considerable progress has been made in surgical and radiation treatment for glioma patients, the impact of these advances on clinical outcome has been disappointing. Therefore, the development of novel therapeutic approaches is essential. Recent reports demonstrate that systemic immunotherapy using dendritic cells (DCs) or peptide vaccines is capable of inducing an antiglioma response. These approaches successfully induce an antitumor immune response and prolong survival in patients with glioma without major side effects. There are several types of glioma, so to achieve effective therapy, it might be necessary to evaluate the molecular genetic abnormalities in individual patient tumors and design novel immunotherapeutic strategies based on the pharmacogenomic findings. Here, we review recent advances in DC- and peptide-based immunotherapy approaches for patients with gliomas.     

Strategies for improving antitumor activity utilizing IL-2: Preclinical models and analysis of antitumor activity of lymphocytes from patients receiving IL-2

Conclusions Considerable enthusiasm remains for the successful utilization of the immune system for the immunotherapy of human cancers. Immunotherapeutic maneuvers have been able to mediate impressive antitumor responses for some patients with advanced and refractory malignancies. Unfortunately, the number of patients who benefit from current immunotherapies is low, while the toxicity for many of the patients receiving these treatments is high. It is becoming quite clear that the development of successful immunotherapeutic strategies will involve a carefully chosen combination of immunotherapeutic modalities or of immunotherapy combined with either surgery, radiation therapy, or chemotherapy. The use of an IL-2 based regimen which is clinically tolerable and can provide significant immune activation continues to remain central to many of these treatment approaches. Preclinicalin vitro and animal model systems can evaluate promising treatment strategies, including combination approaches. As an effective immunotherapeutic approach will likely require use of a combination of biologically active agents, the scheduling of these therapies may have profound importance both for optimal antitumor responses as well as clinical tolerance.     

Translational regulation in the anoxic turtle, <Emphasis Type="Italic">Trachemys scripta elegans</Emphasis>

Liver cancer is the sixth most common cancer worldwide and 3rd most common cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancer and is a major public health problem. Due to the advanced stages of HCC at the time of diagnosis, utilizing the conventional treatment for solid tumors frequently ends with treatment failure, recurrence, or poor survival. HCC is highly refractory to chemotherapy and other systemic treatments, and locoregional therapies or selective internal radiation therapies are largely palliative. Considering how the pathogenesis of HCC often induces an immunosuppressed state which is further amplified by post-treatment recurrence and reactivation, immunostimulation provides a potential novel approach for the treatment of HCC. Immune response(s) of the body may be potentiated by immunomodulation of various effector cells such as B-cells, T-cells, Treg cells, natural killer cells, dendritic cells, cytotoxic T-lymphocytes, and other antigen-presenting cells; cellular components such as genes and microRNA; and molecules such as proteins, proteoglycans, surface receptors, chemokines, and cytokines. Targeting these effectors individually has helped in the development of newer therapeutic approaches; however, combinational therapies targeting multi-faceted biomarkers have yielded better results. Still, there is a need for further research to develop novel therapeutic strategies which may act as either complementary or an alternative treatment to the standard therapy protocols of HCC. This review focuses on potential cellular and molecular targets, as well as the role of virotherapy and combinational therapy in the treatment of HCC.     

肝癌免疫治疗的研究进展

肝细胞肝癌是全球发病率和死亡率最高的恶性肿瘤之一,发病率和死亡率呈逐年上升趋势。我国是肝癌大国,每年肝癌的死亡病例数位居全球第一。免疫治疗是继手术、化疗和放疗之后新兴的癌症治疗手段,其通过解除肿瘤微环境对免疫细胞的抑制作用并激活机体免疫功能,实现控制和杀伤肿瘤细胞。常用的免疫治疗的方法有免疫检查点治疗、过继免疫治疗和肿瘤疫苗治疗等。与传统治疗手段相比,免疫治疗因具有增强机体免疫功能、延缓肿瘤进展、延长患者生存时间等优点,逐渐成为基础和临床研究的热点。文中就免疫治疗在肝癌领域的研究进展作一综述。     

Immune based therapies in cancer

Immunotherapy of cancer has become a more promising approach in the past decade. Developments in both basic immunology and tumor biology have increased our knowledge of the interactions between the tumor cells and the immune system. The molecular identification of tumor-associated antigens and understanding of immunological pathways have cleared the way for development of different strategies for anti-tumor vaccines. The success of any cancer vaccine relies on the induction of an effective tumor-specific immune response to break tolerance and to elicit a long lasting anti-tumor immunity. It is also increasingly clear that the interactions of host-tumor are quite complicated leading to tumor escape mechanisms, which add another level of difficulty to this interaction. This review will summarize the recent developments in tumor immunotherapy as well as the clinical trials addressing novel immunotherapeutic approaches to cancer.     

CD40 immunotherapy for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal cancer which is poorly responsive to standard therapies. Although the PDA tumor microenvironment is considered especially immunosuppressive, recent data mostly from genetically engineered and other mouse models of the disease suggest that novel immunotherapeutic approaches hold promise. Here, we describe both laboratory and clinical efforts to target the CD40 pathway for immunotherapy in PDA. Findings suggest that CD40 agonists can mediate both T-cell-dependent and T-cell-independent immune mechanisms of tumor regression in mice and patients. T-cell-independent mechanisms are associated with macrophage activation and the destruction of PDA tumor stroma, supporting the concept that immune modulation of the tumor microenvironment represents a useful approach in cancer immunotherapy.     

Cancer gene and immunotherapy: recent developments

Gene and immunotherapeutic approaches to treat human malignant tumors are reviewed. Special attention is given to the different strategies of cancer gene therapy and to recent aspects of cytokine-supported tumor immunotherapy or tumor-specific vaccination. The limitations of these therapy approaches are critically discussed especially with respect to immune escape mechanisms.     

Immunotherapy for superficial bladder cancer

The treatment of superficial bladder cancer requires adjuvant therapies besides transurethral resection because of a high recurrence rate after this standard treatment alone. Current adjuvant therapies involve intravesical chemotherapy for patients at low and intermediate risk for recurrence and progression, and intravesical bacillus Calmette-Guérin for patients at intermediate and high risk. However, these adjuvant therapies fail in a significant number of patients, dictating the need for new and improved adjuvant treatment modalities for superficial bladder cancer. Immunotherapy aiming at the modulation of the immune system of the patient is a promising alternative adjuvant. This review discusses the current status of the clinical development of various immunotherapy approaches for superficial bladder cancer, including passive immunotherapy, immune stimulants, immunogene therapy and cancer vaccination.     

Advanced therapeutic modalities in hepatocellular carcinoma: Novel insights

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is usually a latent and asymptomatic malignancy caused by different aetiologies, which is a result of various aberrant molecular heterogeneity and often diagnosed at advanced stages. The incidence and prevalence have significantly increased because of sedentary lifestyle, diabetes, chronic infection with hepatotropic viruses and exposure to aflatoxins. Due to advanced intra- or extrahepatic metastasis, recurrence is very common even after radical resection. In this paper, we highlighted novel therapeutic modalities, such as molecular-targeted therapies, targeted radionuclide therapies and epigenetic modification-based therapies. These topics are trending headlines and their combination with cell-based immunotherapies, and gene therapy has provided promising prospects for the future of HCC treatment. Moreover, a comprehensive overview of current and advanced therapeutic approaches is discussed and the advantages and limitations of each strategy are described. Finally, very recent and approved novel combined therapies and their promising results in HCC treatment have been introduced.     

VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment

Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.     

Therapeutic advances for patients with intermediate hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor and constitutes a major health threat globally. Intermediate HCC (Barcelona Clinic Liver Cancer Staging, stage B) encompasses a wide range of patients and is characterized by substantial heterogeneity with varying tumor burdens and liver functions. Therefore, it is paramount to evaluate the patient's overall conditions and to select the most appropriate therapy based on available evidence. Transarterial chemoembolization is the recommended first-line therapy for intermediate HCC patients. However, in clinical practice, other treatment options are also used as alternative therapies, such as hepatic resection, percutaneous thermal ablation, radiotherapy (RT), systemic treatment, immunotherapy, and so forth. In this review, we will introduce current treatment strategies for intermediate HCC, discuss their advantages and disadvantages, and propose future directions.     

Multimodality treatment resulting in long-term survival in hepatocellular carcinoma.

The early detection and complex therapy of the hepatocellular carcinoma (HCC) is one of the most seasonable questions of the gastroenterology-oncology, because of the increasing prevalence of the primary liver cancer. The course of the hepatocellular carcinoma is rapid, untreated patients rarely live over 5-6 months. Combination of different treatment modalities in HCC can offer the best chances for survival. If possible, a surgical resection should be the primary procedure, followed by adjuvant cytostatic treatment and chemoembolisation. The authors report three cases with HCC with extremely long survival. The long-term survival achieved by multimodality therapy, as presented in these cases, seems to justify aggressive therapeutical approaches in HCC. It has been concluded, that early detection and complex, aggressive multimodality treatment--even repeated liver resections and surgical elimination of duplex distant metastases--can result in long-term survival with a good quality of life.     

Immunotherapy of prostate cancer: identification of new treatments and targets for therapy, and role of WAP domain-containing proteins

Prostate adenocarcinoma is present in over 80% of men over the age of 80 and is by far the most common cancer of men. Although radical prostatectomy is curative in early disease, the risks of incontinence and impotence can affect the quality of life of patients. Early intervention with localized immunotherapy represents a potential solution as lymphocyte infiltration does occur in prostate cancer lesions, and immunotherapy with dendritic cell vaccines can significantly increase survival in late stage disease. However, lymphocytic infiltrates in the cancerous prostates have an anergic character arising from the suppressive effects of the microenvironment resulting from a conversion of effector cells into regulatory T-cells. Although TGFβ (transforming growth factor β) and IL-10 (interleukin-10) are known to be strong suppressor molecules associated with prostate cancer, they are among many possible suppressive factors. We discuss the possible role of alternative suppressor molecules, including the WAP (whey acidic protein) homologue ps20 that is expressed on prostate stroma and other WAP domain-containing proteins in the immunosuppressive prostate cancer milieu and discuss novel immunotherapeutic strategies to combat this disease.     

Long Non-Coding RNAs: Potential Biomarkers and Targets for Hepatocellular Carcinoma Therapy and Diagnosis

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Increasing studies showed that long non-coding RNAs (lncRNAs), a novel class of RNAs that are greater than 200 nucleotides in length but lack the ability to encode proteins, exert crucial roles in the occurrence and progression of HCC. LncRNAs promote the proliferation, migration, invasion, autophagy, and apoptosis of tumor cells by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can be used as biomarkers to predict the efficacy of HCC treatment strategies, such as surgery, radiotherapy, chemotherapy, and immunotherapy, and as a potential individualized tool for HCC diagnosis and treatment. In this review, we overview up-to-date findings on lncRNAs as potential biomarkers for HCC surgery, radiotherapy, chemotherapy resistance, target therapy, and immunotherapy, and discuss the potential clinical application of lncRNA as tools for HCC diagnosis and treatment.     

Integrated Machine Learning and Bioinformatic Analyses Constructed a Novel Stemness-Related Classifier to Predict Prognosis and Immunotherapy Responses for Hepatocellular Carcinoma Patients

Immunotherapy has made great progress in hepatocellular carcinoma (HCC), yet there is still a lack of biomarkers for predicting response to it. Cancer stem cells (CSCs) are the primary cause of the tumorigenesis, metastasis, and multi-drug resistance of HCC. This study aimed to propose a novel CSCs-related cluster of HCC to predict patients'' response to immunotherapy. Based on RNA-seq datasets from The Cancer Genome Atlas (TCGA) and Progenitor Cell Biology Consortium (PCBC), one-class logistic regression (OCLR) algorithm was applied to compute the stemness index (mRNAsi) of HCC patients. Unsupervised consensus clustering was performed to categorize HCC patients into two stemness subtypes which further proved to be a predictor of tumor immune microenvironment (TIME) status, immunogenomic expressions and sensitivity to neoadjuvant therapies. Finally, four machine learning algorithms (LASSO, RF, SVM-RFE and XGboost) were applied to distinguish different stemness subtypes. Thus, a five-hub-gene based classifier was constructed in TCGA and ICGC HCC datasets to predict patients'' stemness subtype in a more convenient and applicable way, and this novel stemness-based classification system could facilitate the prognostic prediction and guide clinical strategies of immunotherapy and targeted therapy in HCC.     

Dendritic cells for specific cancer immunotherapy

The characterization of tumor-associated antigens recognized by human T lymphocytes in a major histocompatibility complex (MHC)-restricted fashion has opened new possibilities for immunotherapeutic approaches to the treatment of human cancers. Dendritic cells (DC) are professional antigen presenting cells that are well suited to activate T cells toward various antigens, such as tumor-associated antigens, due to their potent costimulatory activity. The availability of large numbers of DC, generated either from hematopoietic progenitor cells or monocytes in vitro or isolated from peripheral blood, has profoundly changed pre-clinical research as well as the clinical evaluation of these cells. Accordingly, appropriately pulsed or transfected DC may be used for vaccination in the field of infectious diseases or tumor immunotherapy to induce antigen-specific T cell responses. These observations led to pilot clinical trials of DC vaccination for patients with cancer in order to investigate the feasibility, safety, as well as the immunologic and clinical effects of this approach. Initial clinical studies of human DC vaccines are generating encouraging preliminary results demonstrating induction of tumor-specific immune responses and tumor regression. Nevertheless, much work is still needed to address several variables that are critical for optimizing this approach and to determine the role of DC-based vaccines in tumor immunotherapy.     

Large-scale pharmacogenomic studies and drug response prediction for personalized cancer medicine

The response rate of most anti-cancer drugs is limited because of the high heterogeneity of cancer and the complex mechanism of drug action. Personalized treatment that stratifies patients into subgroups using molecular biomarkers is promising to improve clinical benefit. With the accumulation of preclinical models and advances in computational approaches of drug response prediction, pharmacogenomics has made great success over the last 20 years and is increasingly used in the clinical practice of personalized cancer medicine. In this article, we first summarize FDA-approved pharmacogenomic biomarkers and large-scale pharmacogenomic studies of preclinical cancer models such as patient-derived cell lines, organoids, and xenografts. Furthermore, we comprehensively review the recent developments of computational methods in drug response prediction, covering network, machine learning, and deep learning technologies and strategies to evaluate immunotherapy response. In the end, we discuss challenges and propose possible solutions for further improvement.     

Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization

Necrosis of tumor cells can activate both innate and adaptive antitumor immunity. However, there is little information on the effects of necrosis-inducing cancer treatments on tumor-specific T cell immune responses in humans. We studied the effects of a necrosis-inducing treatment (embolization) on anti-alpha-fetoprotein (AFP)-specific CD4(+) T cell responses in hepatocellular carcinoma (HCC) patients and controls using an array of AFP-derived peptides. In this study, we show that AFP-specific CD4(+) T cell responses to three immunodominant epitopes in HCC patients were significantly expanded during (p < 0.0001) and after embolization (p < 0.002). The development of higher frequencies of AFP-specific CD4(+) T cells after treatment were significantly associated with the induction of >50% necrosis of tumor and an improved clinical outcome (p < 0.007). In addition, we identified two novel HLA-DR-restricted AFP-derived CD4(+) T cell epitopes (AFP(137-145) and AFP(249-258)) and showed that the CD4(+) T cells recognizing these epitopes produce Th1 (IFN-gamma and TNF-alpha) but not Th2 (IL-5)-type cytokines. AFP(137-145)-, AFP(249-258)-, and AFP(364-373)-specific CD4(+) T cells were detected in HCC patients but not in patients with chronic liver diseases or healthy donors. In conclusion; our study shows that induction of tumor necrosis by a conventional cancer treatment can unmask tumor rejection Ag cell-mediated immunity and provides a rationale for combining embolization with immunotherapy in HCC patients.