Immune therapy including dendritic cell based therapy in chronic hepatitis B virus infection

Hepatitis B virus （HBV） infection is a global public health problem. Of the approximately 2 billion people who have been infected worldwide, more than 400 million are chronic carriers of HBV. Considerable numbers of chronic HBV carriers suffer from progressive liver diseases. In addition, all HBV carriers are permanent source of this virus. There is no curative therapy for chronic HBV carriers. Antiviral drugs are recommended for about 10% patients, however, these drugs are costly, have limited efficacy, and possess considerable side effects. Recent studies have shown that immune responses of the host to the HBV are critically involved at every stage of chronic HBV infection： （1） These influence acquisition of chronic HBV carrier state, （2） They are important in the context of liver damages, （3） Recovery from chronic HBV-related liver diseases is dependent on nature and extent of HBV-specific immune responses. However, induction of adequate levels of HBV-specific immune responses in chronic HBV carriers is difficult. During the last one decade, hepatitis B vaccine has been administered to chronic HBV carriers as a therapeutic approach （vaccine therapy）. The present regimen of vaccine therapy is safe and cheap, but not so effective. A dendritic cell-based therapeutic vaccine has recently been developed for treating chronic HBV infection. In this review, we will discuss about the concept, scientific logics, strategies and techniques of development of HBV- specific immune therapies including vaccine therapy and dendritic cell-based vaccine therapy for treating chronic HBV infection.

Effects of combined immune therapy on survival and Th1/Th2 cytokine balance in rat orthotopic liver transplantation

Background The induction of immune tolerance and suppression of allograft rejection has become the focus in the study of liver transplantation. The effect of immune therapy with anti-CD40L mAb alone or in combination with cyclosporine A （CsA） on the recipient survival and Th1/Th2 cytokine profile was studied to elucidate its immunological mechanism and role in rat orthotopic liver transplantation.Methods The model of rat orthotopic liver transplantation was established by modified Kamada＇s technique. Recipients were divided into group A （control group）： SD→SD; group B （group of rejection）： SD→Wistar without any treatment; group C： SD→Wistar with CsA monotherapy from day 1 to day 5; and group D： SD→Wistar with CsA from day 1 to day 5 and anti-CD40L mAb on day 0 and day 2. The survival of the recipients in all groups was observed and ELISA technique was used to detect the level of cytokines in peripheral blood on post-transplant day 7.Results The survival period of recipients in groups A （〉60 days） and D （〉60 days） was significantly longer than that in group B （13.8±2.4 days）. The serum levels of interleukin 2 （IL-2） and interferon y in group B were significantly higher than those in other groups; the level of tumor necrosis factor a was higher but not statistically significant. In contrast, the serum levels of IL-4 and IL-10 in group D were elevated more significantly than those in group B （P〈0.05）.Conclusions Combined immune therapy can prolong the survival of al log rafts. Increased expression of Th2 cytokines, which is closely related to the induction of tolerance and suppression of rejection, is beneficial to the long-term survival of recipients and allografts.

Manipulation of MHC-I/TCR Interaction for Immune Therapy

Adoptive immunotherapy involving the transfer of autologous tumor or virus-reactive T lymphocytes has been demonstrated to be effective in the eradication of cancer and virally infected cells. Identification of MHC-restricted antigens and progress in generation of adaptive immune responses have provided new direction for such treatment for severe pathologies such as cancer and autoimmune diseases. Here we review the latest development about the molecular basis of MHC-I/TCR interaction, and it＇s manipulation including enhanced MHC-I expression, modification of peptide and engineered TCR for clinical applications such as vaccine design, tumor therapy and autoimmune diseases.

Genetic Predisposition to Numerous Large Ulcerating Basal Cell Carcinomas and Response to Immune Therapy

Objective:Well-defined germ-line mutations in thePTCH1 gene are associated with syndromic multiple basal cell carcinomas(BCCs).Here,we used whole exome sequencing(WES)to identify the role of patched-1 in patients with multiple,unusually large BCCs.Methods:A 72-year old patient presenting with numerous BCCs progressing to large ulcerating lesions was enrolled.WES was used to identify the pathogenic gene locus.Results:Genetic work-up by WES identified a homozygousPTCH1 nonsense mutation in the tumor tissue but not present in her blood cells or in non-lesional skin.In addition,heterozygous missense mutations were identified in three cancer-associated genes(EPHB2,RET,andGALNT12)in blood cells as well as in lesional and non-lesional skin.We also tested systemic immune therapy as a potentially beneficial approach to treat patients with numerous large BCCs on scatted areas of involvement.A rapid and sustained response to nivolumab was noted,suggesting that it is an efficacious drug for long-term therapeutic outcome.Conclusion:PTCH1,EPHB2,RET,andGALNT12 may potentially contribute to the synergistic oncogene driven malignant transformation manifesting as multiple,unusually large BCCs.

Current status and hurdles for CAR-T cell immune therapy

Chimeric antigen receptor T(CAR-T)cells have emerged as novel and promising immune therapies for the treatment of multiple types of cancer in patients with hematological malignancies.There are several key components critical for development and application of CAR-T therapy.First,the design of CAR vectors can considerably affect several aspects of the physiological functions of these T cells.Moreover,despite the wide use of g-retrovirus and lentivirus in mediating gene transfer into T cells,optimal CAR delivery systems are also being developed and evaluated.In addition,several classes of mouse models have been used to evaluate the efficacies of CART cells;however,each model has its own limitations.Clinically,although surprising complete remission(CR)rates were observed in acute lymphoblastic leukemia(ALL),lymphoma,and multiple myeloma(MM),there is still a lack of specific targets for acute myeloid leukemia(AML).Leukemia relapse remains a major challenge,and its mechanism is presently under investigation.Cytokine release syndrome(CRS)and neurotoxicity are life-threatening adverse effects that need to be carefully treated.Several factors that compromise the activities of anti-solid cancer CAR-T cells have been recognized,and further improvements targeting these factors are the focus of the development of novel CAR-T cells.Overcoming the current hurdles will lead to optimal responses of CAR-T cells,thus paving the way for their wide clinical application.

Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas

Follicular lymphoma(FL)is the most common indolent B-cell lymphoma(BCL)globally.Recently,its incidence has increased in Europe,the United States,and Asia,with the number of gastrointestinal FL cases expected to increase.Genetic abnormalities related to t(14;18)translocation,BCL2 overexpression,NF-κB pathway-related factors,histone acetylases,and histone methyltransferases cause FL and enhance its proliferation.Meanwhile,microRNAs are commonly used in diagnosing FL and predicting patient prognosis.Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted,resulting in a marked improvement in therapeutic outcomes for FL.Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options,FL treatment has become more complex,requiring combinatorial therapeutic regimens.However,optimal treatment combinations have not yet been achieved,highlighting the importance of a complete understanding regarding the pathogenesis of gastrointestinal FL.Accordingly,this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations.Moreover,the results of clinical trials are summarized,with a particular focus on treating nodal and gastrointestinal FLs.

Hepatocellular carcinoma: Therapy and prevention

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for the development of HCC are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. Despite these scientific advances and the implementation of measures for the early detection of HCC in patients at risk, patient survival has not improved during the last three decades. This is due to the advanced stage of the disease at the time of clinical presentation and limited therapeutic options. The therapeutic options fall into five main categories: surgical interventions including tumor resection and liver transplantation, percutaneous interventions including ethanol injection and radiofrequency thermal ablation, transarterial interventions including embolization and chemoembolization, radiation therapy and drugs as well as gene and immune therapies. These therapeutic strategies have been evaluated in part in randomized controlled clinical trials that are the basis for therapeutic recommendations. Though surgery, percutaneous and transarterial interventions are effective in patients with limited disease (1-3 lesions, ＜5 cm in diameter) and compensated underlying liver disease (cirrhosis Child A), at the time of diagnosis more than 80% patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the therapeutic measures to best supportive care. In order to reduce the morbidity and mortality of HCC, early diagnosis and the development of novel systemic therapies for advanced disease, including drugs, gene and immune therapies as well as primary HCC prevention are of paramount importance. Furthermore, secondary HCC prevention after successful therapeutic interventions needs to be improved in order to make an impact on the survival of patients with HCC. New technologies, including gene expression profiling and proteomic analyses, should allow to further elucidate the molecular events underlying HCC development and to identify novel diagnostic markers as well as therapeutic and preventive targets.

Molecular therapy and prevention of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with an extremely poor prognosis. The major etiologic risk factors for HCC development include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, toxins (alcohol, aflatoxin BI) and various inherited metabolic liver diseases, such as hemochromatosis and alpha-1-antitrypsin deficiency. Central to the molecular pathogenesis of HCC are mutations of various genes and genetic/chromosomal instability that result from chronic liver disease and the associated enhanced liver cell regeneration and mitotic activity. Alterations in the structure or expression of several tumor suppressor genes and oncogenes have been described. In addition, mechanisms leading to genetic instability due to mismatch repair deficiency or chromosomal instability and aneuploidy due to defective chromosomal segregation appear to be involved. The prognosis of HCC patients is generally very poor. Most studies have shown a five-year survival rate of less than 5% in symptomatic patients. HCC has been found to be quite resistant to radio- or chemotherapy. Investigations of the natural history and clinical course of HCC revealed a long-term survival of patients only with small asymptomatic HCC that could be treated surgically or nonsurgically. For patients with advanced symptomatic HCC, novel therapeutic strategies such as gene therapy are urgently needed. Apart from exploring and refining new HCC treatment strategies, the implementation of the existing measures or the development of novel measures to prevent HCC is most important. Primary HCC prevention could have a major impact on the incidence of HCC. Further, secondary prevention of a local recurrence or of new HCC lesions in patients after successful surgical or nonsurgical HCC treatment is of paramount importance and is expected to significantly improve disease-free and overall survival rates of patients. Based on rapid scientific advances, molecular diagnosis, gene therapy and molecular prevention are becoming increasingly part of our patient management and will eventually complement or in part replace the existing diagnostic, therapeutic and preventive strategies. Overall, this should result in a reduced HCC incidence and an improved clinical outcome for patients with HCC, one of the most devastating malignancies worldwide.

CAR T Cell Therapy for Hematological Malignancies

As a rapidly progressing field in oncology,the adoptive transfer of T cells that have been genetically modified with chimeric antigen receptors(CARs)has shown striking efficacy in the management of hematological malignancies and has been reported in a number of clinical trials.of note,CAR T cell therapy has shown extraordinary potential,especially in relapsed/refractory patients.However,there are still challenges regarding the further development of this strategy,spanning from engineering and manufacturing issues,to limited applications,to accompanying toxicities.In this review,we will summarize the general knowledge of this novel method,including receptor composition,applications,adverse events and challenges.Additionally,we will propose several comprehensive recommendations.

Immune phenotypes of prostate cancer cells: Evidence of epithelial immune cell-like transition?

Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-like Transition’’(EIT)by expressing molecules conventionally associated with immune cells(e.g.,a variety of cytokines/receptors,immune transcription factors,Ig motifs,and immune checkpoint molecules),which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment.Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development,thus leading to the development of novel immunotherapeutic approaches.Here,we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells,with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa.Furthermore,we summarize current advances in anti-immune checkpoint therapies,and provide perspectives on their potential applicability.

Early prediction and prevention of infected pancreatic necrosis

Approximately 20%-30%of patients with acute necrotizing pancreatitis develop infected pancreatic necrosis(IPN),a highly morbid and potentially lethal complication.Early identification of patients at high risk of IPN may facilitate appropriate preventive measures to improve clinical outcomes.In the past two decades,several markers and predictive tools have been proposed and evaluated for this purpose.Conventional biomarkers like C-reactive protein,procalcitonin,lymphocyte count,interleukin-6,and interleukin-8,and newly developed biomarkers like angiopoietin-2 all showed significant association with IPN.On the other hand,scoring systems like the Acute Physiology and Chronic Health Evaluation II and Pancreatitis Activity Scoring System have also been tested,and the results showed that they may provide better accuracy.For early prevention of IPN,several new therapies were tested,including early enteral nutrition,anti-biotics,probiotics,immune enhancement,etc.,but the results varied.Taken together,several evidence-supported predictive markers and scoring systems are readily available for predicting IPN.However,effective treatments to reduce the incidence of IPN are still lacking apart from early enteral nutrition.In this editorial,we summarize evidence concerning early prediction and prevention of IPN,providing insights into future practice and study design.A more homo-geneous patient population with reliable risk-stratification tools may help find effective treatments to reduce the risk of IPN,thereby achieving individualized treatment.

Role of chemokines in the hepatocellular carcinoma microenvironment and their translational value in immunotherapy

The difficulty of early diagnosis,high tumor heterogeneity,and high recurrence and metastasis rates lead to an unsatisfactory treatment status for hepatocellular carcinoma(HCC).HCC is a typical inflammation-driven tumor.Chronic inflammation allows nascent tumors to escape immunosurveillance.Chemokines are small,soluble,secreted proteins that can regulate the activation and trafficking of immune cells during inflammation.Several studies have shown that various chemokines with overarching functions disrupt the immune microenvironment during the initiation and progression of HCC.The dysregulated chemokine network in HCC contributes to multiple malignant processes,including angiogenesis,tumor proliferation,migration,invasion,tumor low response,and resistance to immune therapy.Here,we summarize the current studies focusing on the role of chemokines and their receptors in the HCC immune microenvironment,highlighting potential translational therapeutic uses for modulating the chemokine system in HCC.

The heterogeneity of tumor-associated macrophages and strategies to target it

Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.

Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma

Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.

Molecular Therapy and Prevention of Liver Diseases

Molecular analyses have become an integral part of biomedical research as well as clinical medicine. The definition of the genetic basis of many human diseases has led to a better understanding of their pathogenesis and has in addition offered new perspectives for their diagnosis, therapy and prevention. Genetically, human diseases can be classified as hereditary monogenic, acquired monogenic and polygenic diseases. Based on this classification, gene therapy is based on six concepts: (1) gene repair, (2) gene substitution, (3) cell therapy, (4) block of gene expression or function, (5) DNA vaccination and (6) gene augmentation. While major advances have been made in all areas of gene therapy during the last years, various delivery, targeting and safety issues need to be addressed before these strategies will enter clinical practice. Nevertheless, gene therapy will eventually become part of the management of patients with various liver diseases, complementing or replacing existing therapeutic and preventive strategies.

Highlights of Miami winter symposium 2015:into the era of immunotherapy

Personalized cancer medicine has seen significant improvements over the past decade. Recent Elsevier conference： Miami winter symposium 2015 （MWS2015） ＂Towards Personalized Cancer Medicine＂ meeting was dedicated to this exciting field, and focused on new progress in personalized drug development and antibody drug against checkpoint pathway. Tais meeting report summarizes the key developments presented and discussed at the meeting, with a focus on immunotherapy, especially on the CTLA-4 and PD-1/PD-L1 pathways. The monoclonal antibody drugs intervening these checkpoint pathways have the potential to play a larger role in personalize medicine within the near future. Here we intended to provide a comprehensive summary about ongoing trends and future perspectives on personalized medicine in cancer therapy.

Immunotherapy in human colorectal cancer: challenges and prospective

Human colorectal cancer(CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy.

Evaluation of 30 DNA damage response and 6 mismatch repair gene mutations as biomarkers for immunotherapy outcomes across multiple solid tumor types

Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.

Gut microbiota diversity and composition in predicting immunotherapy response and immunotherapy-related colitis in melanoma patients:A systematic review

BACKGROUND Gut microbiome(GM)composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy(ICB)and of ICBrelated colitis.AIM To conduct a systematic review on the role of GM composition and diversity in predicting response and colitis in patients with melanoma treated with ICB.METHODS The review protocol was registered in PROSPERO:CRD42021228018.From a total of 300 studies,nine studies met inclusion criteria.Two studies were phase I clinical trials,while the remainder were prospective observational studies.All but one study has moderate risk of bias.In addition,we conducted a relevant search by Reference Citation Analysis(RCA)(https://www.referencecitationanalysis.com).RESULTS Fecal samples enriched in Firmicutes phylum were associated with good response to ICB,whereas the Bacteroidales family was associated with poor response to ICB.Samples with greater GM diversity were associated with more favorable response to ICB[hazard ratio(HR)=3.57,95%confidence interval=1.02-12.52,P<0.05].Fecal samples with a higher abundance in Firmicutes were more susceptible to ICB-related colitis(P<0.01)whereas samples enriched in Bacteroidetes were more resistant to ICB-related colitis(P<0.05).Overall,there was limited concordance in the organisms in the GM identified to be associated with response to ICB,and studies evaluating GM diversity showed conflicting results.CONCLUSION This highlights the need for further prospective studies to confirm whether the GM could be used as a biomarker and potential intervention to modulate ICB response in melanoma patients.

Porphyrin-based metal-organic framework nanocrystals for combination of immune and sonodynamic therapy

Immune therapy based on programmed death-ligand 1(PD-L1)is widely used to treat human tumors.The current strategies to improve immune checkpoint blockade therapy fail in rescuing increased expression of PD-L1 in tumor issues.Here,we for the first time synthesized the metal-organic framework(MOF)nanocrystals of rare-earth element dysprosium(Dy)coordinated with tetrakis(4-carboxyphenyl)porphyrin(TCPP),which show well-defined two-dimensional morphologies.The MOF nanocrystals of Dy-TCPP could apparently reduce PD-L1 expression in tumor cells both in vitro and in vivo,and therefore display effective tumor treatment through immune therapy without any immune checkpoint inhibitor drugs.Considering the sensitivity of TCPP ligand toward ultrasound,the prepared Dy-TCPP can also realize sonodynamic therapy(SDT)besides immune therapy.In addition,the Dy-TCPP nanocrystals can efficiently obtain T_(2)-weight magnetic resonance imaging(MRI)of tumor sites.Our study provides the Dy-TCPP nanocrystals as promising diagnostic MRI-guided platforms for the combined treatment on tumors with SDT and immune therapy.Moreover,this strategy succeeds in reducing the elevated expression of PD-L1 in tumor cells,which might serve as a novel avenue for tumor immunotherapy in future.