Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of oral cancer (original) (raw)
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Oncology Reports, 2011
Although replication-competent oncolytic viral vectors have been developed to improve antitumor activity, the generation of high titers of neutralizing antibodies inhibits repetitive viral infection. Many studies have reported that oncolytic virus-infected carrier cells can overcome this viral induced immunogenicity. However, the effects of oncolytic virus-infected carrier cells in human oral squamous cell carcinoma (OSCC) have not yet been examined. In the present study, simulating the clinical trial, we examined the antitumor activity of carrier cells infected with oncolytic adenovirus AdE3-IAI.3B in human OSCC. IAI.3B was highly activated in OSCC cells but not in normal cells. AdE3-IAI.3B killed OSCC cells in vitro but not normal cells. AdE3-IAI.3B-infected A549 carrier cells eradicated OSCC GFP-SAS tumors in nude mice. Anti-adenovirus neutralizing antibodies completely blocked the antitumor effect of AdE3-IAI.3B but did not block that of carrier cells. After the induction of anti-adenoviral CTL responses by immunization of adenovirus, administration of carrier cells induced complete regression of murine squamous cell carcinoma SCC7 tumors. Adenovirus-GM-CSF augmented the antitumor effect of carrier cells. The IAI.3B-driven oncolytic adenovirus-infected carrier cell system might prove useful in the treatment of OSCC and clinical trials of it should be conducted in the near future.
Modified adenoviruses for cancer gene therapy
International journal of cancer. Journal international du cancer, 2004
Adenoviral gene therapy is an exciting novel approach for treating cancers resistant to currently available therapies. However, currently there is little evidence supporting significant clinical benefits with replication-incompetent adenoviruses. Recent data suggest that expression of the primary receptor, the coxsackie-adenovirus receptor (CAR), may be highly variable on tumor cells, resulting in resistance to infection. Consequently, various strategies have been evaluated to modify adenovirus tropism in order to circumvent CAR deficiency, including retargeting complexes or genetic capsid modifications. To improve tumor penetration and local amplification on the antitumor effect, selectively oncolytic agents, i.e., conditionally replicating adenoviruses, have been constructed. Infection of tumor cells results in replication, oncolysis and subsequent release of the virus progeny. Normal tissue is spared due to lack of replication. This review focuses on the various modifications tha...
Advances in adenoviral vectors for cancer gene therapy
Expert Opinion on Therapeutic Patents, 1997
Delineation of the molecular basis of cancer affords the possibility of specific intervention at the molecular level for therapeutic purposes. To this end, viral and non-viral vectors have been designed for delivery and expression of genes into target malignant and non-malignant cells. Gene transfer by available vectors, applied in both the ex vivo and in vivo contexts, has resulted frequently in the desired cellular phenotypical changes. In this regard, recombinant adenoviruses have been particularly efficient for in vivo gene transfer. Importantly, numerous human clinical protocols using adenoviruses have rapidly entered into Phase I clinical trials. However, major vector-related problems remain to be solved before the transfer of therapeutic genes by adenoviruses can become an effective and common place strategy for cancer treatment. An overriding obstacle is the basic ability to deliver therapeutic genes quantitatively, and specifically, into tumour cells. In addition, transgene expression in transduced target cells has not been prolonged enough for certain applications. The short-term expression is due both to the adenoviral non-integrative life cycle and to potent inflammatory and immunological responses against the vector and transgene. Here we review a number of diverse advances in the design of adenoviral vectors for overcoming these obstacles. As vector technology fulfils these requirements for obtaining the 'targetable-injectable' vector, it is anticipated that promising results already observed in preclinical studies will translate quickly into the clinic.
Role of Adenoviruses in Cancer Therapy
Frontiers in Oncology, 2022
Cancer is one of the leading causes of death in the world, which is the second after heart diseases. Adenoviruses (Ads) have become the promise of new therapeutic strategy for cancer treatment. The objective of this review is to discuss current advances in the applications of adenoviral vectors in cancer therapy. Adenoviral vectors can be engineered in different ways so as to change the tumor microenvironment from cold tumor to hot tumor, including; 1. by modifying Ads to deliver transgenes that codes for tumor suppressor gene (p53) and other proteins whose expression result in cell cycle arrest 2. Ads can also be modified to express tumor specific antigens, cytokines, and other immune-modulatory molecules. The other strategy to use Ads in cancer therapy is to use oncolytic adenoviruses, which directly kills tumor cells. Gendicine and Advexin are replication-defective recombinant human p53 adenoviral vectors that have been shown to be effective against several types of cancer. Gendicine was approved for treatment of squamous cell carcinoma of the head and neck by the Chinese Food and Drug Administration (FDA) agency in 2003 as a first-ever gene therapy product. Oncorine and ONYX-015 are oncolytic adenoviral vectors that have been shown to be effective against some types of cancer. The Chiness FDA agency has also approved Oncorin for the treatment of head and neck cancer. Ads that were engineered to express immunestimulatory cytokines and other immune-modulatory molecules such as TNF-a, IL-2, BiTE, CD40L, 4-1BBL, GM-CSF, and IFN have shown promising outcome in treatment of cancer. Ads can also improve therapeutic efficacy of immune checkpoint inhibitors and adoptive cell therapy (Chimeric Antigen Receptor T Cells). In addition, different replicationdeficient adenoviral vectors (Ad5-CEA, Ad5-PSA, Ad-E6E7, ChAdOx1-MVA and Adtransduced Dendritic cells) that were tested as anticancer vaccines have been demonstrated to induce strong antitumor immune response. However, the use of adenoviral vectors in gene therapy is limited by several factors such as pre-existing immunity to adenoviral vectors and high immunogenicity of the viruses. Thus, innovative strategies must be continually developed so as to overcome the obstacles of using adenoviral vectors in gene therapy.
Nonreplicating Adenoviral Vectors: Improving Tropism and Delivery of Cancer Gene Therapy
Cancers, 2021
Recent preclinical and clinical studies have used viral vectors in gene therapy research, especially nonreplicating adenovirus encoding strategic therapeutic genes for cancer treatment. Adenoviruses were the first DNA viruses to go into therapeutic development, mainly due to well-known biological features: stability in vivo, ease of manufacture, and efficient gene delivery to dividing and nondividing cells. However, there are some limitations for gene therapy using adenoviral vectors, such as nonspecific transduction of normal cells and liver sequestration and neutralization by antibodies, especially when administered systemically. On the other hand, adenoviral vectors are amenable to strategies for the modification of their biological structures, including genetic manipulation of viral proteins, pseudotyping, and conjugation with polymers or biological membranes. Such modifications provide greater specificity to the target cell and better safety in systemic administration; thus, a ...
Transductional and Transcriptional Targeting of Adenovirus for Clinical Applications
Current Gene Therapy, 2004
Adenovirus (Ad) targeting is a novel approach for the design and administration of therapeutic agents wherein the agent is rationally designed to localize and restrict transgene expression to the site of disease in a self-directed manner, usually via exploitation of unique biophysical and genetic properties specific to the diseased tissue. The ablation of promiscuous native Ad tropism coupled with active targeting modalities has demonstrated that innate gene delivery efficiency may be retained while circumventing Ad dependence on its primary cellular receptor, the coxsackie and adenovirus receptor (CAR), to achieve CAR-independent vector tropism. Herein, we describe advances in Ad targeting that are predicated not only on fundamental understanding of vector/cell interplay, but also on the specific transcriptional profiles of target tissues. Further, targeting is discussed in the context of improving the safety and efficacy of clinical approaches utilizing adenoviral vectors and replication competent oncolytic agents. In summary, existing results suggest a critical linkage between targeted agents and increases in therapeutic utility.
Journal of Virology, 2009
A key impediment to successful cancer therapy with adenoviral vectors is the inefficient transduction of malignant tissue in vivo. Compounding this problem is the lack of cancer-specific targets, coupled with a shortage of corresponding high-efficiency ligands, permitting selective retargeting. The epithelial cell-specific integrin αvβ6 represents an attractive target for directed therapy since it is generally not expressed on normal epithelium but is upregulated in numerous carcinomas, where it plays a role in tumor progression. We previously have characterized a high-affinity, αvβ6-selective peptide (A20FMDV2) derived from VP1 of foot-and-mouth disease virus. We generated recombinant adenovirus type 5 (Ad5) fiber knob, incorporating A20FMDV2 in the HI loop, for which we validated the selectivity of binding and functional inhibition of αvβ6. The corresponding αvβ6-retargeted virus Ad5-EGFP A20 exhibited up to 50-fold increases in coxsackievirus- and-adenovirus-receptor-independent ...
Adenoviral gene therapy in head and neck cancer
Drug News & Perspectives, 2006
Despite advances in surgical techniques, improvement in radiation therapy and the addition of new biological agents such as cetuximab to traditional chemotherapy, the median survival of patients with head and neck cancer has changed little over the past few decades. However, recent advances in the fundamental understanding of head and neck cancer biology suggest that targeting molecular pathways underlying carcinogenesis may provide alternative or additional approaches to the treatment of head and neck cancer. Viruses, particularly adenoviruses, have been critical in the application and development of these molecular approaches. Adenoviruses have been engineered to function as vectors for delivering therapeutic genes for gene therapy. The purpose of this review is to provide a prospective on the use of adenoviruses in head and neck cancer therapy by examining clinical trials of adenovirus-mediated p53 gene therapy and by reviewing the application of a promising oncolytic adenovirus, ONYX-015, in head and neck cancer.
Targeted Adenoviral Vectors for Cancer Gene Therapy
Advances in Experimental Medicine and Biology, 1998
In order to realise the full potential of gene therapy as a rational approach to the treatment of cancer, it will be necessary to achieve delivery of the therapeutic gene selectively to target tumour cells. Such cancer cell-specific gene delivery is mandated in the context of locoregional or compartmentalised carcinomas, and is also an absolute requirement for the treatment of disseminated disease. Moreover, underlying any cancer gene therapy approach is the need to achieve a high level of efficiency of gene transfer to the target cells. Of the existing viral and nonviral gene delivery vehicles, the adeno viral vector uniquely fulfils two requirements of an intra venously administered vector for cancer gene therapy: systemic stability and the ability to accomplish efficient transduction of cancer cells. However, it is necessary to modify native adenoviral tropism in order to achieve selective transduction of target tumour cells. A number of strategies have been developed for this purpose, involving genetic or immunological modifications to either of two adenoviral capsid proteins, the fibre and penton base. These strategies are designed to generate a targetable, injectable vector which would represent a major advance in the field of cancer gene therapy. Contents 1. Introduction: cancer gene therapy 2. Vector requirements for cancer gene therapy 3. The adenovirus is the most promising vector for direct in vivo gene delivery 4. The biology of adenoviral infection 5. The generation of targeted adenoviral vectors by immuno logical modifications of the fibre protein 6. The generation of targeted adenoviral vectors by genetic modifications of the fibre protein 7. The generation of targeted adenoviral vectors by modifications of the penton base 8. Future directions