Special Issue "Gene Therapy Used in Cancer Treatment"

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A special issue of Biomedicines (ISSN 2227-9059).

Deadline for manuscript submissions: closed (15 March 2014)

Special Issue Editor

Guest Editor
Dr. Vincenzo Cerullo (Website)

1 ImmunoViroTherapy Lab (IVTLab), Helsinki, Finland
2 Centre for Drug Research (CDR) and Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
Interests: gene therapy; cancer gene therapy; immunotherapy; immunity; innate immunity; immunovirotherapy; oncolytic viruses; adenovirus; vaccinia virus

Special Issue Information

Dear Colleagues,

This special issue "Gene Therapy for Cancer Treatment" will be mainly focused on the different aspects of cancer gene therapy, gene immunotherapy and immunovirotherapy.
For long time the term "Cancer Gene Therapy" has been mostly referred to oncolytic viruses or viral vector expressing anti-tumor molecules, leaving aside immunotherapy approaches. Nowadays several studies have highlighted the capacity of viral and non-viral approaches to "turn-on" the immune system and the use of this feature to further potentiate the efficacy of the treatment.
More specifically, in this issue papers can be focused on viral and non-viral approaches to cancer therapy, their use as immunotherapy platforms, their modification to increase the safety and/or immunogenicity. Both preclinical and clinical studies will be considered.

Dr. Vincenzo Cerullo
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. For the first couple of issues the Article Processing Charge (APC) will be waived for well-prepared manuscripts. English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • gene therapy
  • cancer gene therapy
  • virotherapy
  • oncolytic viruses
  • immunotherapy
  • cancer vaccines

Published Papers (8 papers)

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Research

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Open AccessArticle Gulonolactone Addition to Human Hepatocellular Carcinoma Cells with Gene Transfer of Gulonolactone Oxidase Restores Ascorbate Biosynthesis and Reduces Hypoxia Inducible Factor 1
Biomedicines 2014, 2(1), 98-109; doi:10.3390/biomedicines2010098
Received: 20 December 2013 / Revised: 26 February 2014 / Accepted: 26 February 2014 / Published: 5 March 2014
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Abstract
Humans are unable to synthesise ascorbate (Vitamin C) due to the lack of a functional gulonolactone oxidase (Gulo), the enzyme that catalyses the final step in the biosynthesis pathway. Ascorbate is a vital micronutrient required for many biological functions, including as a [...] Read more.
Humans are unable to synthesise ascorbate (Vitamin C) due to the lack of a functional gulonolactone oxidase (Gulo), the enzyme that catalyses the final step in the biosynthesis pathway. Ascorbate is a vital micronutrient required for many biological functions, including as a cofactor for metalloenzymes that regulate the transcription factor hypoxia-inducible factor-1 (HIF-1), which governs cell survival under hypoxia. In most animals, ascorbate is made in liver cells. This study aimed to restore ascorbate synthesis to human hepatocellular carcinoma HepG2 cells and determine the effect of internally produced ascorbate on HIF-1 activation. HepG2 cells were gene-modified with a plasmid encoding the mouse Gulo cDNA, tested for genomic incorporation by PCR and ascorbate synthesis by high performance liquid chromatography. Levels of HIF-1 protein were measured using Western blotting. Gulo-modified HepG2 cells showed increased adherence compared to control HepG2 cells. A PCR-positive clone synthesised ascorbate when the Gulo substrate, l-gulono-1,4-lactone, was supplied. Intracellular ascorbate concentrations reached 5% of saturation levels (6 nmol/106 cells). Addition of ascorbate or gulonolactone reduced HIF-1 accumulation in the Gulo clone, but also in parental HepG2 cells. Our data confirm the requirement for a number of factors in addition to Gulo in the ascorbate biosynthesis pathway in human cells. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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Review

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Open AccessReview Lentivirus-Induced Dendritic Cells (iDC) for Immune-Regenerative Therapies in Cancer and Stem Cell Transplantation
Biomedicines 2014, 2(3), 229-246; doi:10.3390/biomedicines2030229
Received: 14 April 2014 / Revised: 29 July 2014 / Accepted: 4 August 2014 / Published: 21 August 2014
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Abstract
Conventional dendritic cells (cDC) are ex vivo differentiated professional antigen presenting cells capable of potently stimulating naïve T cells and with vast potential for immunotherapeutic applications. The manufacture of clinical-grade cDC is relatively complex and requires several days for completion. Clinical trials [...] Read more.
Conventional dendritic cells (cDC) are ex vivo differentiated professional antigen presenting cells capable of potently stimulating naïve T cells and with vast potential for immunotherapeutic applications. The manufacture of clinical-grade cDC is relatively complex and requires several days for completion. Clinical trials showed poor trafficking of cDC from subcutaneous injection sites to lymph nodes (LN), where DC can optimally stimulate naïve lymphocytes for long-lasting memory responses. We demonstrated in mouse and human systems that a single overnight ex vivo lentiviral (LV) gene transfer into DC precursors for production of combination of cytokines and antigens was capable to induce autonomous self-differentiation of antigen-loaded DC in vitro and in vivo. These highly viable induced DC (iDC) effectively migrated from the injected skin to LN, where they effectively activated de novo antigen-specific effector memory T cells. Two iDC modalities were validated in relevant animal models and are now in clinical development: Self-differentiated Myeloid-derived Antigen-presenting-cells Reactive against Tumors co-expressing GM-CSF/IL-4/TRP2 for melanoma immunotherapy in the autologous setting (SmartDCtrp2), and Self-differentiated Myeloid-derived Lentivirus-induced against human cytomegalovirus as an allogeneic matched adoptive cell after stem cell transplantation (SmyleDCpp65). The lentiviral vector design and packaging methodology has “evolved” continuously in order to simplify and optimize function and biosafety of in vitro and in vivo genetic reprogramming of iDC. Here, we address the challenges seeking for new creations of genetically programmed iDC and integrase-defective LV vaccines for immune regeneration. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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Open AccessReview Toll-Like Receptor 9 Agonists for Cancer Therapy
Biomedicines 2014, 2(3), 211-228; doi:10.3390/biomedicines2030211
Received: 17 April 2014 / Revised: 24 July 2014 / Accepted: 28 July 2014 / Published: 4 August 2014
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Abstract
The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 [...] Read more.
The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC) and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs) have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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Open AccessReview Tumor Restrictions to Oncolytic Virus
Biomedicines 2014, 2(2), 163-194; doi:10.3390/biomedicines2020163
Received: 18 February 2014 / Revised: 17 March 2014 / Accepted: 28 March 2014 / Published: 17 April 2014
Cited by 2 | PDF Full-text (2157 KB) | HTML Full-text | XML Full-text
Abstract
Oncolytic virotherapy has advanced since the days of its conception but therapeutic efficacy in the clinics does not seem to reach the same level as in animal models. One reason is premature oncolytic virus clearance in humans, which is a reasonable assumption [...] Read more.
Oncolytic virotherapy has advanced since the days of its conception but therapeutic efficacy in the clinics does not seem to reach the same level as in animal models. One reason is premature oncolytic virus clearance in humans, which is a reasonable assumption considering the immune-stimulating nature of the oncolytic agents. However, several studies are beginning to reveal layers of restriction to oncolytic virotherapy that are present before an adaptive neutralizing immune response. Some of these barriers are present constitutively halting infection before it even begins, whereas others are raised by minute cues triggered by virus infection. Indeed, we and others have noticed that delivering viruses to tumors may not be the biggest obstacle to successful therapy, but instead the physical make-up of the tumor and its capacity to mount antiviral defenses seem to be the most important efficacy determinants. In this review, we summarize the constitutive and innate barriers to oncolytic virotherapy and discuss strategies to overcome them. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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Open AccessReview Gene Therapy Used in Cancer Treatment
Biomedicines 2014, 2(2), 149-162; doi:10.3390/biomedicines2020149
Received: 15 January 2014 / Revised: 12 March 2014 / Accepted: 18 March 2014 / Published: 8 April 2014
Cited by 2 | PDF Full-text (210 KB) | HTML Full-text | XML Full-text
Abstract
Cancer has been, from the beginning, a target of intense research for gene therapy approaches. Currently, more than 60% of all on-going clinical gene therapy trials worldwide are targeting cancer. Indeed, there is a clear unmet medical need for novel therapies. This [...] Read more.
Cancer has been, from the beginning, a target of intense research for gene therapy approaches. Currently, more than 60% of all on-going clinical gene therapy trials worldwide are targeting cancer. Indeed, there is a clear unmet medical need for novel therapies. This is further urged by the fact that current conventional cancer therapies are frequently troubled by their toxicities. Different gene therapy strategies have been employed for cancer, such as pro-drug activating suicide gene therapy, anti-angiogenic gene therapy, oncolytic virotherapy, gene therapy-based immune modulation, correction/compensation of gene defects, genetic manipulation of apoptotic and tumor invasion pathways, antisense, and RNAi strategies. Cancer types, which have been targeted with gene therapy, include brain, lung, breast, pancreatic, liver, colorectal, prostate, bladder, head and neck, skin, ovarian, and renal cancer. Currently, two cancer gene therapy products have received market approval, both of which are in China. In addition, the stimulation of the host’s immune system, using gene therapeutic approaches, has gained vast interest. The intention of this review is to point out the most commonly viral and non-viral vectors and methods used in cancer gene therapy, as well as highlight some key results achieved in clinical trials. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
Open AccessReview Challenges and Prospects for Helper-Dependent Adenoviral Vector-Mediated Gene Therapy
Biomedicines 2014, 2(2), 132-148; doi:10.3390/biomedicines2020132
Received: 6 February 2014 / Revised: 7 March 2014 / Accepted: 18 March 2014 / Published: 2 April 2014
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Abstract
Helper-dependent adenoviral (HDAd) vectors that are devoid of all viral coding sequences are promising non-integrating vectors for gene therapy because they efficiently transduce a variety of cell types in vivo, have a large cloning capacity, and drive long-term transgene expression without [...] Read more.
Helper-dependent adenoviral (HDAd) vectors that are devoid of all viral coding sequences are promising non-integrating vectors for gene therapy because they efficiently transduce a variety of cell types in vivo, have a large cloning capacity, and drive long-term transgene expression without chronic toxicity. The main obstacle preventing clinical applications of HDAd vectors is the host innate inflammatory response against the vector capsid proteins that occurs shortly after intravascular vector administration and result in acute toxicity, the severity of which is dose dependent. Intense efforts have been focused on elucidating adenoviral vector–host interactions and the factors involved in the acute toxicity. This review focuses on the recent acquisition of data on such interactions and on strategies investigated to improve the therapeutic index of HDAd vectors. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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Open AccessReview Feasibility of Applying Helper-Dependent Adenoviral Vectors for Cancer Immunotherapy
Biomedicines 2014, 2(1), 110-131; doi:10.3390/biomedicines2010110
Received: 20 December 2013 / Revised: 25 February 2014 / Accepted: 26 February 2014 / Published: 10 March 2014
Cited by 1 | PDF Full-text (742 KB) | HTML Full-text | XML Full-text
Abstract
Adenoviruses (Ads) infect a broad range of tissue types, and derived vectors have been extensively used for gene therapy. Helper-dependent Ad vectors (HDAds), devoid of viral coding sequences, allow for insertion of large or multiple transgenes in a single vector and have [...] Read more.
Adenoviruses (Ads) infect a broad range of tissue types, and derived vectors have been extensively used for gene therapy. Helper-dependent Ad vectors (HDAds), devoid of viral coding sequences, allow for insertion of large or multiple transgenes in a single vector and have been preclinically used for the study of genetic disorders. However, the clinical application of Ad vectors including HDAds for genetic disorders has been hampered by an acute toxic response. This characteristic, while disadvantageous for gene replacement therapy, could be strategically advantageous for the activation of an immune response if HDAds were used as an adjunct treatment in cancer. Cancer treatments including immunotherapy are frequently limited by the inhibitory environment produced by both tumors and their stroma, each of which express numerous inhibitory molecules. Hence, multiple inhibitory mechanisms must be overcome for development of anti-tumor immunity. The large coding capacity of HDAds can accommodate multiple immune modulating transgenes that could produce a combined effect to overcome tumor-derived inhibition and ensure intratumoral effector T-cell proliferation and function. In this review, we discuss the potential advantages of HDAds to cancer immunotherapy based on potent host immune responses to Ads. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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Open AccessReview Oncolytic Adenoviruses in Cancer Treatment
Biomedicines 2014, 2(1), 36-49; doi:10.3390/biomedicines2010036
Received: 15 January 2014 / Revised: 13 February 2014 / Accepted: 14 February 2014 / Published: 21 February 2014
Cited by 4 | PDF Full-text (310 KB) | HTML Full-text | XML Full-text
Abstract
The therapeutic use of viruses against cancer has been revived during the last two decades. Oncolytic viruses replicate and spread inside tumors, amplifying their cytotoxicity and simultaneously reversing the tumor immune suppression. Among different viruses, recombinant adenoviruses designed to replicate selectively in [...] Read more.
The therapeutic use of viruses against cancer has been revived during the last two decades. Oncolytic viruses replicate and spread inside tumors, amplifying their cytotoxicity and simultaneously reversing the tumor immune suppression. Among different viruses, recombinant adenoviruses designed to replicate selectively in tumor cells have been clinically tested by intratumoral or systemic administration. Limited efficacy has been associated to poor tumor targeting, intratumoral spread, and virocentric immune responses. A deeper understanding of these three barriers will be required to design more effective oncolytic adenoviruses that, alone or combined with chemotherapy or immunotherapy, may become tools for oncologists. Full article
(This article belongs to the Special Issue Gene Therapy Used in Cancer Treatment)
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