Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer

Fujita, Tetsuo; Timme, Terry L.; Tabata, Ken Ichi; Naruishi, Koji; Watanabe, Masami; Abdelfattah, E.; Zhu, Jessica; Ren, Chengzhen; Yang, Guang; Goltsov, Alexei A.; Wang, H.; Vlachaki, María T.; Teh, Bin S.; Butler, E. Brian; Thompson, Timothy C.

doi:10.1038/sj.gt.3302788

Cited by 16 publications

(27 citation statements)

References 45 publications

(65 reference statements)

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“…It has been shown that the antitumor efficacy of RT/IL-12 depends on the presence of T and NK cells. 17,18,22 In this study, our data showed that RT/IL-12 treatment significantly increased the numbers of tumor-infiltrating CD8 + T cells with potent cytotoxic activities (Figure 6(a)), as demonstrated by their increased surface expression of CD107a. 26 For tumor-infiltrating NK cells, although the number was not significantly changed post RT/IL-12 treatment, these cells were highly active in the cytotoxic phenotype as demonstrated by their up to 30-fold increase in CD107a expression (Figure 6(b)).…”

Section: Discussionsupporting

confidence: 51%

“…This is consistent with the observation that RT synergizes with the antitumor effects of IL-12 in various experimental animal models. 15–18,22,33 Our study further extends this combination strategy to treat HCC.…”

Section: Discussionmentioning

confidence: 53%

“…18,22 Therefore, we determined how RT/IL-12 influenced effector functions of tumor-infiltrating CD8 + T cells and NK cells by examining their production of intracellular IFN-γ and TNF-α and membrane expression of CD107a, a measure of effector cell degranulation associated with perforin/granzyme-dependent cytotoxicity. To obtain cell status that reflects their in vivo activities at the time of tumor harvest, these effector lymphocytes were directly analyzed by flow cytometry without ex vivo restimulation.…”

Section: Resultsmentioning

confidence: 99%

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Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

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Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver per se may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities. Our data showed that radiation and IL-12 combination therapy (RT/IL-12) led to dramatic tumor regression in animals bearing large subcutaneous or orthotopic HCC, induced systemic effect against distant tumor, and significantly prolonged survival. Radiation monotherapy induced tumor regression at early times but afterwards most tumors regained exponential growth, while IL-12 monotherapy only delayed tumor growth. Mechanistic studies revealed that RT/IL-12 increased expression of MHC class II and co-stimulatory molecules CD40 and CD86 on tumor-infiltrating dendritic cells, suggesting an improvement of their antigen presentation activity. RT/IL-12 also significantly reduced accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing production of reactive oxygen species. Accordingly, tumor-infiltrating CD8+ T cells and NK cells were significantly activated toward the antitumor phenotype, as revealed by increased expression of CD107a and TNF-α. Together, our data showed that RT/IL-12 treatment could reset the intratumoral immunotolerant state and stimulate activation of antitumor cellular immunity that is capable of eliminating large established HCC tumors.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

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Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

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“…Liu previously demonstrated that transferrin receptors were overexpressed on PC-3, DU145 and LNCaP cells, with a higher level of expression on the surface of PC-3 cells [13]. therapeutic effect on prostate tumors, but following intratumoral injection rather than intravenous administration, while using a viral delivery system rather than a non-viral one, and often in conjunction with other therapeutic modalities, such as radiotherapy [28], co-administration with oncolytic herpes simplex viruses [29], with adenoviral vector-mediated Herpes Simplex Virus / thymidine kinase and ganciclovir [30], or in addition with the drug mifepristone [31]. For example, the intratumoral administration of an adenoviral vector encoding the TRAIL gene under the control of FLT1 promoter, in combination with radiation treatment, was shown to produce significant slowdown of the growth of DU145 tumor xenografts in athymic nude mice [25].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of Intravenously Administered Transferrin-Conjugated Dendriplexes on Prostate Carcinomas

et al. 2014

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This version is available at https://strathprints.strath.ac.uk/42676/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. would be an attractive anti-cancer treatment strategy, however the lack of suitable carrier systems able to selectively deliver therapeutic genes to tumors has so far limited this investigation. Given that transferrin receptors are overexpressed on prostate cancer cells, the purpose of this study is to determine whether transferrinbearing dendriplex encoding TNF±, TRAIL and IL-12 would suppress the growth of prostate cancer cell lines in vitro and in vivo. TITLE Materials & Methods:Transferrin-bearing dendriplexes encoding TNF±, TRAIL and IL-12 were intravenously administered to mice bearing subcutaneous PC-3 and DU145 tumors. Results:The administration of the DAB-Tf dendriplex encoding TNF± resulted in tumor suppression for 60% of PC-3 and 50% of DU145 prostate tumors. Conclusions:These dendriplexes hold great potential as a novel approach for prostate cancer therapy. KEYWORDS 4 MATERIALS & METHODS Cell lines and reagents Preparation of transferrin-bearing polypropylenimine dendrimerGeneration 3-diaminobutyric polypropylenimine dendrimer (DAB, 24 mg) was conjugated to transferrin (Tf, 6 mg) by cross-linking with dimethylsuberimidate (DMSI, 12 mg) in triethanolamine HCl buffer (pH 7.4, 2 mL), as previously described 8 Statistical AnalysisResults were expressed as means ± standard error of the mean (S.E.M). Statistical significance was assessed by one-way analysis of variance (ANOVA) and Bonferroni multiple comparison post-test (GraphPad Prism software). P values lower than 0.05 were considered statistically different. 9 RESULTS Cellular uptake of DNAConfocal microscopy experiments confirmed that Cy3-labelled DNA was taken up by PC-3, DU145 and LNCaP cells (Figure 1). The fluorescently-labeled DNA was found to be disseminated in the cytoplasm following treatment with DAB-Tf and DAB dendriplexes in the three teste...

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“…Similar results were obtained in subsequent studies combining IL-12 gene therapy and radiotherapy. [53][54][55] TNF-α is another attractive candidate for cancer gene therapy since it encodes for secretory protein with a broad range of potent anti-tumor properties, which include induction of the immune system, enhancement of radiosensitivity, direct cytotoxicity and disruption of the tumor vasculature. 56 An additive killing effect of systemic recombinant TNF-α administration and radiation was reported in a MCA-K mouse tumor model.…”

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confidence: 99%

Targeted gene therapy in radiotherapy

Kamenšek¹,

Serša²

2008

Radiology and Oncology

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out of the primary tumor are not destroyed. In addition, there are some radio-resistant cells within a single tumor mass that may survive despite a relatively high radiation dose. The efficacy of radiotherapy is also limited by chronic and intermittent hypoxia in the tumors.To increase the efficacy of radiotherapy, while minimizing its side effects, developments have been made in combining radiotherapy with chemotherapy and, lately, gene therapy. Gene therapy and its combination with radiotherapyGene therapy consists of the transfer of exogenous genes, called transgenes, into human somatic cells and the expression of these genes in transfected cells for a therapeutic purpose. In cancer treatment, this means either correction of genetic defects, characteristic of cancer cells, or induction of targeted tumor cell death. 3 In gene correction or replacement approach, a defective or inactivated tumor suppressor gene is replaced, for example to increase radiation-induced apoptosis (wild-type p53 replacement therapy) or high oncogene expression levels are repressed with the use of antisense, ribozymes or siRNA technology. However, because cancer is a consequence of countless genetic mutations, most anti-tumor therapies aim to destroy cancer cells, rather than correct these complex defects. Strategies to destroy cancer cells can be exerted in different ways; by gene directed chemotherapy, potentiation of immune response and targeting of the tumor vasculature (Table 1). Recent advances in gene therapy approaches have allowed researchers to successfully combine gene therapy with radiotherapy. 4,5 There are many potential benefits of combining radiotherapy with gene therapy:• Gene therapy and radiotherapy techniques have different mechanisms of action and they target best at different parts of the cell cycle, which may result in an additive effect ( Figure 1).• Gene therapy can cause radiosensitization, which means that a synergistic (supra-additive) anti-tumor effect is possible ( Figure 1).• Radiation can enhance the "bystander effect" of gene therapy, meaning that more Gene therapy strategy GenesGenetic replacement or correction therapy p53, CTS1, MDA7, Suicide gene therapy (gene chemotherapy) Endogenous precursors HSV-tk, CD, CD/HSV-tk fusion, HRP, IAA Exogenous precursors iNOS Gene based immunotherapy TNF-α, IFN-γ, IL-12…, tumor associated antigens (PSA)Vascular-targeted gene therapy VEGF-antisense, soluble endostatin, angiostatin, vazostatin, CTS1, Chimeric Tumor Suppressor 1 (synthetic variant of wild-type p53); HSV-tk, Herpes Simplex Virus thymidine kinase; CD, Cytosine Deaminase; HRP, Horseradish Peroxidase; IAA, Indol-3-Acetic Acid; iNOS, inducible Nitric Oxide Synthase; TNF-α, Tumor Necrosis Factor-α; IL-12, Interleukin-12; PSA, Prostate Specific Antigen; VEGF, Vascular Endothelial Growth Factor. Radiol Oncol 2008; 42(3): . Unauthenticated Download Date | 5/9/18 6:42 PM cells are affected by gene therapy than are transfected initially. This is probably because of the release of products of therapeutic g...

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Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer

Cited by 16 publications

References 45 publications

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Therapeutic Efficacy of Intravenously Administered Transferrin-Conjugated Dendriplexes on Prostate Carcinomas

Targeted gene therapy in radiotherapy

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