Gene-Based Therapies for Cancer (Current Cancer Research)

Generally, there is still not much long-term safety data using viral vectors in humans. Nevertheless, several meta-analysis already exist for adenoviruses demonstrating an adequate safety profile in humans [ 41 , 43 ]. The tolerability towards adenoviral vectors has been acceptable and the side effects have mostly been mild without any serious adverse events related to gene therapy. Different means with the intention of improving the safety of gene therapy have been implemented.

One approach is to develop targeting strategies in order to enhance the delivery of gene transfer vectors, and hence, to improve the duration and efficacy of gene expression. Generally, one of the major shortcomings with gene therapy is their lack of specificity to their target cells and their low transduction efficiency. Consequently, the improvement of transduction efficacy of gene transfer vectors has come along with the development of vector technologies, including re-engineering of viral vectors using epitope insertion, chemical modification, and molecular evolution [ 44 ].

An example for this was demonstrated in a phase I clinical trial by Kim et al. The role of innate immunity, as well as the activation of T and B cells in response to the vector and its transgene product is a topic of intense research. The pre-existence of neutralizing antibodies e. In order to improve specificity, as well as transduction efficiency, viral surface proteins have been modified, removed or replaced. For example, lentiviral vectors have been generated, wherein a cell type specific ligand or antibody has been fused to the viral envelope i. The downside of this has been that different modifications resulted in low vector titers during lentivirus production [ 13 ].

Furthermore, it has been shown that targeting may also potentially compromise the entry of the vector into the cell [ 13 , 47 ]. On the contrary to targeting viral vectors to specific cells, pseudotyping can also be used to broaden tropism of the viral vector to other cells. For example, retroviruses and lentiviruses are frequently pseudotyped with the Vesicular Stomatitis virus G-protein VSV-G to widen their tropism and to increase their yield in production [ 48 ].

Another approach to increase specificity of viral vectors to their target cells is the use of tissue-specific or conditional promoters. An example for conditional dependent gene expression is the use of hypoxia-specific regulatory systems, where gene expression is aimed to be induced and restricted to ischemic tissues [ 49 ]. Commonly, these hypoxia-specific regulatory systems have been applied to various ischemic disease models, including ischemic myocardium, stroke, and injured spinal cord, but could also be used in cancer gene therapy [ 50 ].

Gene expression can also be regulated based on a genotypic feature e. The risk of insertional mutagenesis with integrating vectors is a safety risk. Retroviruses, lentiviruses and AAVs are examples of viruses that integrate their genome into their host chromosomes. By doing so, there is a chance that these vectors may integrate into gene regulatory areas or into transcriptionally active areas, respectively, which potentially can adversely result in insertional mutagenesis and oncogenesis.

Several approaches have been developed to circumvent these problems. Therefore, targeted integration of transgenes to predetermined genomic sites has been one of the most important topics in current vector development. One of the most efficient methods to achieve targeted integration into human cells is based on DNA double-strand break-enhanced homologous recombination [ 51 ]. For example, the Sleeping Beauty transposon system is an attractive approach allowing stable integration of the transgene through transposition into the target cell genome [ 53 , 54 ].

However, the fact, that conventional cancer therapies i. It is fact that many chemotherapeutic drugs, as well as radiation therapy, may cause genetic alterations and oncogenesis in patients [ 55 , 56 , 57 ]. In addition, by developing the manufacturing of gene transfer vectors i. For example, gutless adenoviral vectors are vectors, where all other genes but those essential for virus production are removed and replaced with the gene of interest, driven by a suitable promoter.

As a result, gutless adenoviruses still exhibit high transduction efficiency and similar tropism to previous vectors, but are less immunogenic than the first generation adenoviral vectors. However, since gutless vectors are devoid of all viral genes, co-infection with a helper adenovirus is required that provides proteins needed for its genome replication, packaging, and capsid formation. As both helper and gutless vectors have the same viral capsid, separation must be addressed before purification, which is laborious and has not been without challenges [ 58 ].

Gene therapy is an intriguing and potential approach to treat various diseases, including cancer. Currently most gene therapy protocols are limited to the local administration of the gene transfer vector, or to ex vivo gene transfer approaches. One of the challenges in gene therapy is still the low transduction efficiency and its minimal distribution of the vector within the tissue. However, it should be emphasized that focus should not only be directed towards vector development itself, but also towards the manufacturing of these vectors.

The high cost involved in viral vector manufacturing, which is the result of tedious downstream purifications steps, has been challenging. In addition, the concept of using gene therapy as a single agent therapy has not been as successful as being hoped. Consequently, combination therapy with existing conventional modalities or other new therapies should be considered and may offer additional benefit in cancer gene therapy.

National Center for Biotechnology Information , U. Journal List Biomedicines v. Published online Apr 8. Thomas Wirth 1 A. Author information Article notes Copyright and License information Disclaimer. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license http: This article has been cited by other articles in PMC. Abstract Cancer has been, from the beginning, a target of intense research for gene therapy approaches.

Introduction Cancer is a major global health problem accounting, annually, for more than eight million deaths globally. Gene Therapy for Cancer: An Overview Rogers et al. Gene Transfer Methods and Vectors Used for Gene Therapy The challenge in gene therapy is to deliver an adequate amount of genetic material into target cells or tissues and to maintain gene expression for a desired period of time.

Viral Vectors The most commonly used viral vectors used for gene transfer are adenoviruses, lenti- and retroviruses including the human immunodeficiency virus HIV , vaccinia viruses, adeno associated viruses AAV , and baculoviruses. Non-Viral Vectors Viral vectors have been shown to be efficient gene transfer tools. Clinical Efficacy of Gene Therapy Different gene therapy approaches using different gene transfer vectors have been studied for cancer gene therapy.

Gene Therapeutic Approaches to Stimulate the Immune System Immunotherapy is a topic that has gained much attention recently. Pro-Drug Activating Suicide Gene Therapy The principle of pro drug activating suicide gene therapy is to introduce a transgene encoding for an enzyme that is either absent in mammalian cells or present in a very inactive form, into the tumor. Safety of Gene Therapy Despite the tragic case of Jesse Gelsinger, who died as a result of gene therapy using adenoviral vectors, the safety data collected from different human gene therapy trials have been uniformly satisfactory.

Conclusions Gene therapy is an intriguing and potential approach to treat various diseases, including cancer. Conflicts of Interest The authors declare no conflict of interest. The hallmarks of cancer. A proposed role of the microenvironment in restraining cancer progression. Use of viruses as carriers of added genetic information. Induction of arginase activity with the Shope papilloma virus in tissue culture cells from an argininemic patient.

Unsuccessful trial of gene replacement in arginase deficiency. Gene transfer into humans—Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. Improving safety of gene therapy. Tropism-modification strategies for targeted gene delivery using adenoviral vectors.

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Gene therapy | Cancer in general | Cancer Research UK

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Gene Therapy Used in Cancer Treatment

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Technol Cancer Res Treat.

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A fiber-modified, secretory leukoprotease inhibitor promoter-based conditionally replicating adenovirus for treatment of ovarian cancer. Combining high selectivity of replication with fiber chimerism for effective adenoviral oncolysis of CAR-negative melanoma cells. A selective cytotoxic for prostate-specific antigen- positive prostate cancer cells. Induction of arginase activity with Shope papilloma virus in tissue-culture cells from an argininemic patient. Use of viruses as carriers of added genetic information.

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Unique conditionally replication competent bipartite adenoviruses-cancer terminator viruses CTV: Efficacious reagents for cancer gene therapy. A cancer terminator virus eradicates both primary and distant human melanomas. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Targeted virus replication plus immunotherapy eradicates primary and distant pancreatic tumors in nude mice. Novel cancer growth suppressing and apoptosis inducing cytokine. Some viruses infect and kill cells. Researchers are working on ways to change these viruses so they only target and kill cancer cells, leaving healthy cells alone.

This sort of treatment uses the viruses to kill cancer cells directly rather than to deliver genes. So it is not cancer gene therapy in the true sense of the word. But doctors sometimes refer to it as gene therapy. It uses a strain of the cold sore virus herpes simplex virus that has been changed by altering the genes that tell the virus how to behave.

1. Introduction

It tells the virus to destroy the cancer cells and ignore the healthy cells. T-VEC is now available as a treatment for melanoma skin cancer. It is also being looked at in trials for head and neck cancer. You have T-VEC as an injection directly into the melanoma or head and neck cancer. About Cancer generously supported by Dangoor Education since Call freephone or email us.

Skip to main content. General cancer information Treatment for cancer. Gene therapy is a cancer treatment that is still in the early stages of research. What genes are Genes are coded messages that tell cells how to make proteins. Boosting the immune response. There are a few trials using this type of gene therapy in the UK.