Emerging frontiers in immuno- and gene therapy for cancer

Background aimsThe field of cell and gene therapy in oncology has moved rapidly since 2017 when the first cell and gene therapies, Kymriah followed by Yescarta, were approved by the Food and Drug Administration in the United States, followed by multiple other countries. Since those approvals, several new products have gone on to receive approval for additional indications. Meanwhile, efforts have been made to target different cancers, improve the logistics of delivery and reduce the cost associated with novel cell and gene therapies. Here, we highlight various cell and gene therapy-related technologies and advances that provide insight into how these new technologies will speed the translation of these therapies into the clinic.ConclusionsIn this review, we provide a broad overview of the current state of cell and gene therapy-based approaches for cancer treatment – discussing various effector cell types and their sources, recent advances in both CAR and non-CAR genetic modifications, and highlighting a few promising approaches for increasing in vivo efficacy and persistence of therapeutic drug products.     

Targeted gene modification for gene therapy of stem cells

Ideally, gene therapy would correct the specific gene defect without adding potentially harmful extraneous DNA sequences. Such correction can be obtained with homologous recombination between input DNA sequences and identical (homologous) sequences in the genomic target gene. The development of techniques for obtaining virtually pure populations of hematopoietic stem cells should permit the use of the highly efficient nuclear microinjection methods for transfer of DNA. These techniques combined with new highly sensitive methods for detecting cells with the specified genetic modification of nonexpressed genes would make homologous recombination-mediated gene therapy feasible for hematopoietic stem cells. These advances are reviewed with particular emphasis on approaches to targeted gene modification of hematopoietic stem cells and speculation on directions for future research.     

Targeted therapy in breast cancer: the HER-2/neu gene and protein

The HER-2/neu oncogene, a member of the epidermal growth factor receptor or erb gene family, encodes a transmembrane tyrosine kinase receptor that has been linked to prognosis and response to therapy with the anti-HER-2-humanized monoclonal antibody, trastuzumab (Herceptin, Genentech, South San Francisco, CA) in patients with advanced metastatic breast cancer. HER-2/neu status has also been tested for its ability to predict the response of breast cancer to other therapies including hormonal therapies, topoisomerase inhibitors, and anthracyclines. This review includes an analysis of 80 published studies encompassing more than 25,000 patients designed to consider the relative advantages and disadvantages of the various methods of measuring HER-2/neu in clinical breast cancer specimens. Southern blotting, PCR amplification detection, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is reviewed along with the current studies designed to test whether HER-2/neu status can predict the response to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review will also evaluate the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.     

Targeted gene therapy for rat glomerulonephritis using HVJ-immunoliposomes

Background

Kidney targeted gene transfer has been attempted by many researchers over the last 10 years; however, unfortunately, no reliable technique for gene transfer to the kidney has been established. At experimental level several in vivo gene transfer methods have been reported.

Methods

We were the first to report successful in vivo gene transfer into the kidney using the HVJ‐liposome method. Since then, this method has been modified to achieve highly efficient gene transfer. In this study, we have developed a renal glomerulus‐specific gene transfer method using HVJ‐liposomes with anti‐Thy 1 antibody, OX‐7.

Results

Following systemic delivery of fluoroisothiocyanate (FITC)‐labeled oligodeoxynucleotides (ODN) by HVJ‐liposomes coupled with OX‐7, we observed fluorescence in renal glomeruli from 2 h post‐administration. To examine the efficacy of this delivery system, NF‐κB or scrambled (SD) decoy ODN was administered by HVJ‐liposomes coupled with OX‐7 into a crescent glomerulonephritis, anti‐g lomerular b asement m embrane (GBM) model. Animals given SD decoy ODN developed severe glomerulonephritis by day 7 with heavy albuminuria, glomerular crescent formation and up‐regulated renal expression of IL‐1β and ICAM‐1. In contrast, NF‐κB decoy ODN treatment substantially inhibited the disease with a reduction in alubuminuria, histological damage and the renal expression of inflammatory cytokines.

Conclusions

This study has demonstrated that systemic delivery of HVJ‐liposomes coupled with OX‐7 results in efficient ODN transfer in rat glomeruli. NF‐κB, but not SD decoy ODN administered systemically via HVJ‐liposomes complexed with OX‐7 showed clear therapeutic potential for glomerulonephritis. This novel ODN transfer method combined with decoy strategy has the potential to lead to the establishment of a new therapeutic approach to glomerular diseases. Copyright © 2002 John Wiley & Sons, Ltd.

     

Targeted deletion of the sciellin gene resulted in normal development and maturation

Sciellin, together with other precursor proteins, was cross-linked by transglutaminase 1 to form the cornified envelope, an essential component of the physical barrier of the epidermis and stratified squamous epithelia. To more fully understand the function of sciellin in cornified envelope formation, we generated sciellin null mice. The mice appeared normal in their development and maturation and there were no structural features that distinguished them from littermate controls. Isolated cornified envelopes appeared normal in structure and were not more fragile to mechanical stress. There was no evidence of decreased barrier function or altered expression of other cornified envelope components. Transgenic mice expressing the repeat domain appeared to have a normal phenotype, like the null, and did not alter endogenous sciellin expression. We conclude that sciellin null mice had no structural anomalies and the transgenic mice did not act as a dominant-negative mutation.     

Targeted vectors for gene therapy of cancer and retroviral infections

Gene therapy has developed to a technology which rapidly moved from the laboratory bench to the bedside in the clinic. This implies safe, efficient and targeted gene transfer systems for suitable application to the patient. Beside the development of such gene transfer vectors of viral or nonviral origin, improvement of cell type specific and inducible gene expression is pivotal for successful gene therapy leading to targeted gene action. Numerous gene therapy approaches for treatment of cancer and retroviral infections utilize cell type specific and/or regulatable promoter and enhancer sequences for the selective expression of therapeutic genes in the desired cell populations and tissues. In this article the recent developments and the potential of expression targeting are reviewed for gene therapy approaches of cancer and retroviral infections.     

From nutraceutical to clinical trial: frontiers in Ganoderma development

Ganoderma spp. are medical mushrooms with various pharmacological compounds which are regarded as a nutraceutical for improving health and treating diseases. This review summarizes current progress in the studies of Gamoderma ranging from bioactive metabolites, bioactivities, production techniques to clinical trials. Traditionally, polysaccharides and ganoderic acids have been reported as the major bioactive metabolites of Ganoderma possessing anti-tumor and immunomodulation functions. Moreover, recent studies indicate that Gandoerma also exerts other bioactivities such as skin lighting, gut microbiota regulation, and anti-virus effects. However, since these medical fungi are rare in natural environment, and that the cost of cultivation of fruiting bodies is high, industrial submerged fermentation of Ganoderma mycelia promotes the development of Ganoderma by dint of an increase of biomass and bioactive metabolites used for further application. In addition, various strategies for production of different metabolites are well developed, such as gene regulation, bi-stage pH, and oxygen control. To date, Ganoderma not only has become one of the most popular nutraceuticals worldwide but also has been applied to clinical trials for advanced diseases such as breast and non-small-cell lung cancer.

     

Evaluation of anti-coccidial drugs' inhibition of Neospora caninum development in cell cultures

Eight anti-coccidial drugs were examined for their efficacies in preventing development of Neospora caninum in bovine monocyte cell cultures. Lasalocid sodium (0.05 microgram/ml), monensin sodium (0.05 microgram/ml), piritrexim (0.01 microgram/ml), pyrimethamine (0.05 microgram/ml), and trimethoprim (5.0 micrograms/ml) were effective in preventing development of intracellular N. caninum tachyzoites (P less than 0.05). No differences (P greater than 0.05) in mean numbers of infected cells compared to controls were observed in cultures treated with amprolium hydrochloride (10.0 micrograms/ml), sulfadiazine (200.0 micrograms/ml), and sulfamethoxazole (200.0 micrograms/ml).     

Targeted therapy for colorectal cancer: mapping the way

In spite of the significant advances in conventional therapeutic approaches to colorectal cancer (CRC), most patients ultimately die of their disease. Dissecting the molecular mechanisms underlying CRC progression will not only accelerate the development of novel cancer-selective drugs but will also enable the therapeutic regimen to be personalized according to the molecular features of individual patients and tumors. Here, we report on the novel insights into CRC biology that are paving the way to the development of molecular therapies and summarize the results from recent clinical trials demonstrating that agents targeting tumor-specific molecular derangements can significantly improve the therapeutic efficacy of conventional chemotherapy. Only a broader clinical implementation of these concepts will provide patients with CRC the best chance of a cure.     

Latest development in viral vectors for gene therapy

Gene therapy includes the application of various viral vectors, which represent most types and families of viruses, suitable for infection of mammalian host cells. Both hereditary diseases and acquired illnesses, such as cancer, can be targeted. Because of the various properties of each viral vector, the definition of their application range depends on factors such as packaging capacity, host range, cell- or tissue-specific targeting, replication competency, genome integration and duration of transgene expression. Recent engineering of modified viral vectors has contributed to improved gene delivery efficacy.     

Targeted gene delivery: the role of peptide nucleic acid

Receptor-mediated endocytosis can be exploited to achieve efficient cell-specific gene delivery. Our laboratory has used two approaches for targeted gene delivery. One uses polycation as a carrier for plasmid DNA and the other uses peptide nucleic acid (PNA) as a carrier. Targeted gene delivery using polycation carriers has been widely utilized with some success. This approach mainly suffers from large particle size and non-specific interaction with blood components. These drawbacks have limited use of this type of vector forin vivo applications. Using PNA as a carrier, on the other hand, allows for smaller particle size and less non-specific interactions. The stability of this vector in the circulation may be a limiting factor. In addition, both types of vector lack mechanisms for endosome escape and nuclear transport. In this chapter, current developments and uses for targeted gene delivery of each approach are reviewed.     

Targeted gene delivery: the role of peptide nucleic acid

Receptor-mediated endocytosis can be exploited to achieve efficient cell-specific gene delivery. Our laboratory has used two approaches for targeted gene delivery. One uses polycation as a carrier for plasmid DNA and the other uses peptide nucleic acid (PNA) as a carrier. Targeted gene delivery using polycation carriers has been widely utilized with some success. This approach mainly suffers from large particle size and non-specific interaction with blood components. These drawbacks have limited use of this type of vector for in vivoapplications. Using PNA as a carrier, on the other hand, allows for smaller particle size and less non-specific interactions. The stability of this vector in the circulation may be a limiting factor. In addition, both types of vectorlack mechanisms for endosome escape and nuclear transport. In this chapter, current developments and uses for targeted gene delivery of each approach are reviewed.     

Targeted therapy in the treatment of solid tumors: Practice contradicts theory

The basic principle of targeted therapy formulated about ten years ago consists in the design and application of drugs specifically directed against well-defined targets that are critical for tumor survival and not compromising for normal organs and tissues. The past decade has been marked by the appearance of an immense diversity of novel antitumor agents with claimed targeted action. Unfortunately, despite indisputable progress in clinical settings, some popular drugs against solid tumors (e.g. bevacizumab, trastuzumab, erlotinib, gefitinib) nominally assigned to targeted-action drugs, cannot actually be classified with this group being nonconforming to a priori stated goals of targeted therapy. The state-of-the-art and current problems in targeted therapy of solid tumors are reviewed.