腺相关病毒载体在肺疾病基因治疗中的应用

腺相关病毒（adeno-associated virus,AAV）载体具有安全性好、免疫原性低、能感染分裂细胞和非分裂细胞、能介导基因的长期稳定表达等优点。因此,作为一种基因导入系统,重组AAV载体在基因治疗的研究和开发中受到越来越多的关注和重视。本文着重就重组AAV载体在肺部疾病基因治疗中的应用以及改进重组AAV载体的策略作简要综述。     

Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice

Long-term cures of hemophilia B have been achieved using AAV2 delivering the factor IX gene to the liver of adeno-associated virus (AAV)-naive hemophilic animals. However, the clinical success of this approach requires overcoming pre-existing AAV neutralizing antibodies prevalent in humans. To better define the inhibition of neutralizing antibodies on AAV2-mediated liver transduction, we developed an in vivo passive immunity model. SCID mice were first reconstituted to a defined neutralizing titer with pooled plasma-derived human immunoglobulin. AAV2-FIX vectors then were administered to the liver, and the transduction efficiency was measured by plasma FIX levels. Unexpectedly, AAV2 neutralizing titers lower than 1:10 were sufficient to neutralize 4 to 20 x 10(12) vg/kg of AAV2 vectors in vivo, a capacity that was underestimated by in vitro neutralizing assays. We also evaluated strategies to evade neutralization, including the use of alternative delivery routes, infusion parameters, empty capsids, and alternative AAV serotypes 6 and 8. The results indicate that low AAV2 neutralizing titers can be inhibitory to the tested human and primate AAV vectors delivered into the circulatory system. Therefore, novel nonprimate AAV vectors or compartmentalized delivery may offer more consistent therapeutic effects in the presence of pre-existing AAV neutralizing antibodies.     

Current status of gene therapy for cystic fibrosis pulmonary disease

Cystic fibrosis (CF) is a common lethal genetic disorder that affects all ethnic populations; however, it is most prevalent in Caucasians. Intensive basic research over the last 20 years has resulted in a wealth of information regarding the CF gene, its protein product and the mutational basis of disease. This increased understanding has lead to the development of gene therapy for the treatment of CF pulmonary disease. Delivery of the CF gene to the airway requires direct in vivo transfer using vectors encoding for normal CF transmembrane regulator (CFTR) protein. Several vectors are currently available for CF gene transfer and include both viral (adenoviruses, adeno-associated viruses) and non-viral (liposomal) systems. Initial clinical trials with each of these vectors have demonstrated that gene transfer to the CF airway is possible. The efficiency of transfer and duration of expression, however, have been limited. The effects of gene transfer on correction of the basic ion transport defects have also been highly variable and inconsistent, irrespective of the vector. Currently, the risk of severe immunological reactions is the primary factor limiting the clinical advancement of gene therapy. Both the adenoviral and liposomal vectors are associated with significant acute inflammatory reactions. The adenoviruses and adeno-associated viruses also elicit humoral immune responses that significantly reduce the efficiency of transgene expression and increase the risk of readministration. Several strategies are under investigation to improve the efficiency of gene transfer to the CF airway. These include overcoming local barriers in the lung, circumventing the immune response and improving vector internalization and/or uptake. Application of gene transfer in the child and possibly the fetus are also potential future clinical applications of gene therapy. However, despite considerable research with gene therapy, there is little evidence to suggest that a well tolerated and effective gene transfer method is imminent and aggressive use of conventional pharmacological therapies currently offer the greatest promise in the treatment of patients with CF.     

Serotype chimeric human adenoviruses for cancer gene therapy

Cancer gene therapy consists of numerous approaches where the common denominator is utilization of vectors for achieving therapeutic effect. A particularly potent embodiment of the approach is virotherapy, in which the replication potential of an oncolytic virus is directed towards tumor cells to cause lysis, while normal cells are spared. Importantly, the therapeutic effect of the initial viral load is amplified through viral replication cycles and production of progeny virions. All cancer gene therapy approaches rely on a sufficient level of delivery of the anticancer agent into target cells. Thus, enhancement of delivery to target cells, and reduction of delivery to non-target cells, in an approach called transductional targeting, is attractive. Both genetic and non-genetic retargeting strategies have been utilized. However, in the context of oncolytic viruses, it is beneficial to have the specific modification included in progeny virions and hence genetic modification may be preferable. Serotype chimerism utilizes serotype specific differences in receptor usage, liver tropism and seroprevalence in order to gain enhanced infection of target tissue. This review will focus on serotype chimeric adenoviruses for cancer gene therapy applications.     

Outer retinal transduction can be achieved after intravitreal delivery of adeno-associated virus serotype 2 vector with glycosidic enzymes

BackgroundGene therapies for retinal disorders, including in current clinical trials, so far have relied on subretinal delivery of adeno-associated virus (AAV) vectors carrying therapeutic DNA into outer retinal cells. Subretinal injection has many limitations over the less-invasive route of administration into the vitreal cavity. However, at present only limited retinal transduction can be achieved after intravitreal delivery of AAV vectors. We hypothesise that the inner limiting membrane and extracellular matrix proteoglycans act as a barrier to AAV vector entry into and movement across the retina. Therefore, glycosidic enzymes, which degrade these extracellular barriers, can improve retinal gene therapy. In this study we investigated the effects of enzymatic digestion of extracellular matrices on the depth of vector penetration into the retina.MethodsThe green fluorescent protein (GFP)-expressing AAV serotype 2 (AAV2) vector was co-injected intravitreally with glycosidic enzymes at their optimum concentration. Efficacy of virus transduction was assessed by visualising fluorescence in histological cross-sections with fluorescence microscopy. We also analysed safety of these treatments and retinal function using electroretinography.FindingsGlycosidic enzymes led to a significant improvement in retinal transduction after intravitreal delivery of AAV2. These enzymes markedly improved transduction of the outer retina, including photoreceptor cells. Electroretinograms were unchanged (compared with controls) even at much higher doses of enzymes than were needed for optimum retinal transduction.InterpretationAAV2-mediated retinal transduction is improved by co-injection of glycosidic enzymes into the vitreous. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to the inner and outer retina in both preclinical and clinical settings.FundingUK Medical Research Council.     

Vectors selected from adeno-associated viral display peptide libraries for leukemia cell-targeted cytotoxic gene therapy

OBJECTIVE: For acute myeloid leukemia (AML), gene therapy may be used to treat patients refractory to conventional chemotherapy. However, availability of vectors sufficiently and specifically transducing this cell type is very limited. METHOD: Here we report the selection of capsid-modified adeno-associated viral (AAV) vectors targeting Kasumi-1 AML cells by screening random AAV displayed peptide libraries. RESULTS: The peptide inserts of the enriched capsid mutants share a common sequence motif. The same motif was selected in an independent library screening on HL-60 AML cells. Recombinant targeted vectors displaying the selected peptides transduced the target leukemia cells they have been selected on up to 500-fold more efficiently compared to AAV vectors with control peptide inserts. One of the selected clones (NQVGSWS) also efficiently transduced all members of a panel of four other AML cell lines. Binding and blocking experiments showed that NQVGSWS binding to leukemia cells is independent of the wild-type AAV-2 receptor heparin sulfate proteoglycan. Transduction assays on a panel of hematopoietic and nonhematopoietic cell lines showed that the NQVGSWS capsid was able to overcome resistance to AAV transduction, especially in hematopoietic cancer cells, whereas normal peripheral blood mononuclear cells and CD34(+) hematopoietic progenitor cells were not transduced. CONCLUSIONS: Consequently, recombinant targeted NQVGSWS AAV vectors harboring a suicide gene conferred selective killing to Kasumi-1 cells, but not to control cells. This suggests that the AAV mutant selected here may be used as a tool to target therapeutic genes to AML cells.     

Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs

Hemophilia A, a deficiency of functional coagulation factor VIII (FVIII), is treated via protein replacement therapy. Restoring 1% to 5% of normal blood FVIII activity prevents spontaneous bleeding, making the disease an attractive gene therapy target. Previously, we have demonstrated short-term activity of a liver-specific AAV2 vector expressing canine B-domain-deleted FVIII (cFVIII) in a hemophilia canine model. Here, we report the long-term efficacy and safety of AAV-cFVIII vectors of serotypes 2, 5, 6, and 8 in both hemophilia A mice and dogs. AAV6-cFVIII and AAV8-cFVIII restored physiologic levels of plasma FVIII activity in hemophilia A mice. The improved efficacy is attributed to more efficient gene transfer in liver compared with AAV2 and AAV5. However, supraphysiologic cFVIII levels correlated with the formation of cFVIII-neutralizing antibodies in these mice. Of importance, hemophilia A dogs that received AAV2-cFVIII, AAV6-cFVIII, and AAV8-cFVIII have persistently expressed therapeutic levels of FVIII, without antibody formation or other toxicities, for more than 3 years. However, liver transduction efficiencies are similar between AAV2, AAV6, and AAV8 serotypes in hemophilia A dogs, in contrast to mice. In summary, this is the first report demonstrating multiyear therapeutic efficacy and safety of multiple AAV-cFVIII vectors in hemophilia A dogs and provides the basis for human clinical studies.     

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.     

Gene therapy of cancer

Gene therapy was initially thought of as a means to correct single gene defects in hereditary disease. In the meantime, cancer has become by far the most important indication for gene therapy in clinical trials. In the foreseeable future, the best way to achieve reasonable intratumoral concentrations of a transgene with available vectors is direct intratumoral injection with or without the aid of various techniques such as endoscopy or CT-guidance. At present, viral and non-viral methods of gene transfer are used either in vivo or ex vivo/in vitro. The most important viral vectors currently in use in clinical trials comprise retroviruses, adenoviruses, adeno-associated viruses, and herpes viruses. None of the available vectors satisfies all the criteria of an ideal gene therapeutic system, and vectors with only minimal residues of their parent viruses ("gutless vectors") as well as completely "synthetic viral vectors" will gain more and more importance in the future. Non-viral gene therapy methods include liposomes, injection of vector-free DNA ("naked DNA"), protein-DNA complexes, delivery by "gene gun," calcium-phosphate precipitation, electroporation, and intracellular microinjection of DNA. The first clinical trial of gene therapy for cancer was performed in 1991 in patients with melanoma, and since then more than 5000 patients have been treated worldwide in more than 400 clinical protocols. With the exception of a case of fatal toxicity in a young man with hereditary liver disease treated intrahepatically with high doses of adenovirus, side effects have been rare and usually mild in all these studies and expression of the transgene could be demonstrated in patients in vivo. However, despite anecdotal reports of therapeutic responses in some patients, unequivocal proof of clinical efficacy is still lacking for most of the varied approaches to gene therapy in humans. As well as our only fragmentary understanding of the molecular pathophysiology of many diseases, the principal reason for the present lack of clinical success of gene therapy is the very low transduction and expression efficiency in vivo of available vectors. Despite the complexities of gene therapy for cancer, the numerous different approaches can be subdivided into three basic concepts: (1) strengthening of the immune response against a tumour, (2) repair of cell cycle defects caused by losses of tumour suppressor genes or inappropriate activation of oncogenes, and (3) suicide gene strategies. In addition, the importance of gene marker studies and gene therapeutic protection of normal tissue are briefly covered in this review.     

Trans-splicing vectors expand the utility of adeno-associated virus for gene therapy

Adeno-associated viral (AAV) vectors have demonstrated considerable promise for gene therapy of inherited diseases. However, with a packaging size of <5 kb, applications have been limited to relatively small disease genes. Based on the finding that AAV genomes undergo intermolecular circular concatamerization after transduction in muscle, we have developed a paradigm to increase the size of delivered transgenes with this vector through trans-splicing between two independent vectors coadministered to the same tissue. When two vectors encoding either the 5' or 3' portions of the erythropoietin genomic locus were used, functional erythropoietin protein was expressed in muscle subsequent to the formation of intermolecular circular concatamers in a head-to-tail orientation through trans-splicing between these two independent vector genomes. These findings will allow for the application of AAV technologies to a wider variety of diseases for which therapeutic transgenes exceed the packaging limitation of present AAV vectors.     

Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model

Duchenne muscular dystrophy (DMD) is the most common and lethal genetic muscle disorder, caused by recessive mutations in the dystrophin gene. One of every 3,500 males suffers from DMD, yet no treatment is currently available. Genetic therapeutic approaches, using primarily myoblast transplantation and adenovirus-mediated gene transfer, have met with limited success. Adeno-associated virus (AAV) vectors, although proven superior for muscle gene transfer, are too small (5 kb) to package the 14-kb dystrophin cDNA. Here we have created a series of minidystrophin genes (<4.2 kb) under the control of a muscle-specific promoter that readily package into AAV vectors. When injected into the muscle of mdx mice (a DMD model), two of the minigenes resulted in efficient and stable expression in a majority of the myofibers, restoring the missing dystrophin and dystrophin-associated protein complexes onto the plasma membrane. More importantly, this AAV treatment ameliorated dystrophic pathology in mdx muscle and led to normal myofiber morphology, histology, and cell membrane integrity. Thus, we have defined minimal functional dystrophin units and demonstrated the effectiveness of using AAV to deliver the minigenes in vivo, offering a promising avenue for DMD gene therapy.     

Adenoviral gene therapy in hepatocellular carcinoma: a review

Background

Hepatocellular carcinoma is the third leading cause of cancer death. Single or multiple mutations in genes related to growth control, apoptosis, invasion and metastasis have been determined; so a better understanding of the molecular genetic basis of malignant transformation, tumor progression and host interaction has led to significant progress in the development of new therapeutic agents. The ability of adenovirus vectors to deliver and express genes at high yields in HCC treatment has been demonstrated and well documented over the last few years.

Objective

To overview and provide an update of what has been accomplished in the field of adenoviral gene therapy and its application in hepatocellular carcinoma treatment.

Methods

Original articles were searched using Pubmed and other medical databases to get the most representative and actual information to establish the current state of the investigation of Ad vectors in HCC.

Results

Good results have been accomplished in preclinical models using new Ad vectors and especially AAV vectors, it is important to motivate further clinical trials to corroborate all the experience obtained.

Conclusions

Ad and AAV must be considered as an opportunity to improve the quality of life and survival of HCC patients.     

Transduction of hepatocellular carcinoma (HCC) using recombinant adeno-associated virus (rAAV): in vitro and in vivo effects of genotoxic agents

BACKGROUND/AIMS: Adeno-associated virus (AAV) is an attractive tool for gene therapy. Here we investigated the in vitro and in vivo transduction of hepatocellular carcinoma (HCC) cells by an AAV vector and the efficacy of different strategies to enhance the transduction of the tumor. METHODS: Transduction efficiency was determined by analyzing AAV-mediated beta-galactosidase gene (rAAV/lacZ) expression. RESULTS: Adenovirus help or pretreatment of HCC cells with y-irradiation or with the topoisomerase inhibitor etoposide resulted in marked enhancement of cell transduction in vitro. In vivo studies in nude mice with subcutaneous HCC tumors showed that HCC cells were not transduced by AAV vector alone. However, co-infection of the tumor with adenovirus allowed an efficient expression of the reporter gene but only at the sites of vector injection. Previous gamma-irradiation of subcutaneous tumors with 1800 rad was able to improve transduction of HCC cells (up to 30%) using recombinant AAV. Continuous i.p. infusion of etoposide in buffalo rats harboring HCC tumors in the liver resulted in transduction of normal liver tissue and also of very small neoplastic lesions (<2 mm) but no transduction was observed in tumors bigger than 2 mm. To analyze this phenomenon we determined etoposide concentration in hepatic tissue. Our results revealed high concentrations of the drug in non-tumoral tissue but almost undetectable levels in big tumor nodules. CONCLUSIONS: Our results indicate that while both radiotherapy and etoposide enhance transduction of tumor cells by rAAV in vitro, only radiotherapy increases tumor transduction in vivo. Our data suggest the existence of a barrier which limits in vivo the diffusion of chemotherapeutic agents to well-established HCC nodules.     

Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein

Somatic gene therapy has been proposed as a means to achieve systemic delivery of therapeutic proteins. However, there is limited evidence that current methods of gene delivery can practically achieve this goal. In this study, we demonstrate that, following a single intramuscular administration of a recombinant adeno-associated virus (rAAV) vector containing the β-galactosidase (AAV-lacZ) gene into adult BALB/c mice, protein expression was detected in myofibers for at least 32 weeks. A single intramuscular administration of an AAV vector containing a gene for human erythropoietin (AAV-Epo) into mice resulted in dose-dependent secretion of erythropoietin and corresponding increases in red blood cell production that persisted for up to 40 weeks. Primary human myotubes transduced in vitro with the AAV-Epo vector also showed dose-dependent production of Epo. These results demonstrate that rAAV vectors are able to transduce skeletal muscle and are capable of achieving sustained expression and systemic delivery of a therapeutic protein following a single intramuscular administration. Gene therapy using AAV vectors may provide a practical strategy for the treatment of inherited and acquired protein deficiencies.     

Species D Adenoviruses as Oncolytic Viral Vectors

Oncolytic adenoviruses (Ad) have shown promising results in the therapeutic treatment of cancer. Ad type 5 (Ad5) is the most extensively utilized Ad type. However, several limitations exist to using Ad5 as an oncolytic virus, including high levels of anti-Ad5 neutralizing antibodies in the population, binding of the Ad5 hexon to blood coagulation factor X leading to liver sequestration and toxicity, and reduced expression of the primary receptor CAR on many tumors. Here, we use in vitro methods to explore the oncolytic potential of four alternative Ad types (Ad26, 28, 45, and 48) belonging to the species D Ad subgroup and developed replication-competent species D Ads expressing the human sodium iodide symporter protein (hNIS) for combination radiovirotherapy. We evaluated the species D Ad vectors transduction, replication, cytotoxicity, and gene expression in six different cancer cell lines. Species D Ads showed the greatest transduction and cytotoxic killing in the SKBR3 breast cancer cells, followed by 293, A549, and HepG2 cells, however the cytotoxicity was less than the wild type Ad5 virus. In contrast, species D Ads showed limited transduction and cytotoxicity in the Hela and SKOV3 cancer cell lines. These species D Ad vectors also successfully expressed the hNIS gene during infection leading to increased iodide uptake in multiple cancer cell lines. These results, the low seroprevalence of anti-species D antibodies, and the lack of binding to blood coagulation FX, support further exploration of species D Ads as alternative oncolytic adenoviruses against multiple types of cancer.     

Gene therapy for monogenic liver diseases: clinical successes,current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics.     

Adeno-associated virus (AAV) vectors achieve prolonged transgene expression in mouse myocardium and arteries in vivo: a comparative study with adenovirus vectors

Plasmid DNA and adenovirus vectors currently used in cardiovascular gene therapy trials are limited by low efficiency and short-lived transgene expression, respectively. Recombinant adeno-associated virus (AAV) has recently emerged as an attractive vector for cardiovascular gene therapy. In the present study, we have compared AAV and adenovirus vectors with respect to gene transfer efficiency and the duration of transgene expression in mouse hearts and arteries in vivo. AAV vectors (titer: 5×10⁸ transducing units (TU)/ml) and adenovirus vectors (1.2×10¹⁰ TU/ml) expressing a green fluorescent protein (EGFP) gene were injected either intramyocardially (n=32) or intrapericardially (n=3) in CD-1 mice. Hearts were harvested at varying time intervals (3 days to 1 year) after gene delivery. After intramyocardial injection of 5 μl virus stock solution, cardiomyocyte transduction rates with AAV vectors were 4-fold lower than with adenovirus vectors (1.5% (range: 0.5–2.6%) vs. 6.2% (range: 2.7–13.7%); P<0.05), but similar to titer-matched adenovirus vectors (0.7%; range: 0.2–1.2%). AAV-mediated EGFP expression lasted for at least 1 year. AAV vectors instilled into the pericardial space transduced epicardial myocytes. Arterial gene transfer was studied in mouse carotids (n=26). Both vectors selectively transduced endothelial cells after luminal instillation. Transduction rates with AAV vectors were 8-fold lower than with adenovirus vectors (2.0% (range: 0–3.2%) vs. 16.2% (range: 8.5–20.2%); P<0.05). Prolonged EGFP expression was observed after AAV but not adenovirus-mediated gene transfer. In conclusion, AAV vectors deliver and express genes for extended periods of time in the myocardium and arterial endothelium in vivo. AAV vectors may be useful for gene therapy approaches to chronic cardiovascular diseases.     

Adenovirus Biology,Recombinant Adenovirus,and Adenovirus Usage in Gene Therapy

Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer cells, and COVID-19 vaccines have recently been commercialized. Recombinant adenoviruses, including replication-defective adenoviral vector and conditionally replicating adenovirus (CRA; oncolytic adenovirus), have been extensively studied and used in clinical trials for cancer and vaccines. Here, we review the biology of wild-type adenoviruses, the methodological principle for constructing recombinant adenoviruses, therapeutic applications of recombinant adenoviruses, and new technologies in pluripotent stem cell (PSC)-based regenerative medicine. Moreover, this article describes the technology platform for efficient construction of diverse “CRAs that can specifically target tumors with multiple factors” (m-CRAs). This technology allows for modification of four parts in the adenoviral E1 region and the subsequent insertion of a therapeutic gene and promoter to enhance cancer-specific viral replication (i.e., safety) as well as therapeutic effects. The screening study using the m-CRA technology successfully identified survivin-responsive m-CRA (Surv.m-CRA) as among the best m-CRAs, and clinical trials of Surv.m-CRA are underway for patients with cancer. This article also describes new recombinant adenovirus-based technologies for solving issues in PSC-based regenerative medicine.     

Conversion therapy in liver transplantation for hepatocellular carcinoma: What's new in the era of molecular and immune therapy?

BackgroundHepatocellular carcinoma (HCC) is the sixth most common cancer globally, with limited therapies and unsatisfactory prognosis once in the advanced stages. With promising advances in locoregional and systematic treatments, fast development of targeted drugs, the success of immunotherapy, as well as the emergence of the therapeutic alliance, conversion therapy has recently become more well developed and an effective therapeutic strategy. This article aimed to review recent developments in conversion therapy in liver transplantation (LT) for HCC.Data sourcesWe searched for relevant publications on PubMed before September 2022, using the terms “HCC”, “liver transplantation”, “downstaging”, “bridging treatment” and “conversion therapy.”ResultsConversion therapy was frequently represented as a combination of multiple treatment modalities to downstage HCC and make patients eligible for LT. Although combining various local and systematic treatments in conversion therapy is still controversial, growing evidence has suggested that multimodal combined treatment strategies downstage HCC in a shorter time, which ultimately increases the opportunities for LT. Moreover, the recent breakthrough of immunotherapy and targeted therapy for HCC also benefit patients with advanced-stage tumors.ConclusionsIn the era of targeted therapy and immunotherapy, applying the thinking of transplant oncology to benefit HCC patients receiving LT is a new topic that has shed light on advanced-stage patients. With the expansion of conversion therapy concepts, further investigation and research is required to realize the full potential of conversion treatment strategies, including accurately selecting candidates, determining the timing of surgery, improving the conversion rate, and guaranteeing the safety and long-term efficacy of treatment.