A Novel Conditionally Replicative Adenovirus Vector Targeting Telomerase-Positive Tumor Cells

Huang, Qian; Zhang, Xiuwu; Wang, He; Yan, Binggong; Kirkpatrick, John P.; Dewhrist, Mark W.; Li, Chuan-Yuan

doi:10.1158/1078-0432.ccr-03-0122

Cited by 53 publications

(32 citation statements)

References 22 publications

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“…Selective cytolysis of telomerase-positive cells was observed and administration of the viral mutant to tumor xenografts resulted in significant inhibition of tumor growth. 94,95 Growth factor receptors are also often upregulated in tumor cells. One study showed that an adenovirus mutant, containing the E1 gene under control of a vascular endothelial growth factor receptor (flt-1) promoter, was specifically targeted to teratocarcinoma cell lines.…”

Section: Viral Dependency On Tissue/tumor-specific Promotersmentioning

confidence: 99%

Replication-selective oncolytic viruses in the treatment of cancer

2004

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In the search for novel strategies, oncolytic virotherapy has recently emerged as a viable approach to specifically kill tumor cells. Unlike conventional gene therapy, it uses replication competent viruses that are able to spread through tumor tissue by virtue of viral replication and concomitant cell lysis. Recent advances in molecular biology have allowed the design of several genetically modified viruses, such as adenovirus and herpes simplex virus that specifically replicate in, and kill tumor cells. On the other hand, viruses with intrinsic oncolytic capacity are also being evaluated for therapeutic purposes. In this review, an overview is given of the general mechanisms and genetic modifications by which these viruses achieve tumor cell-specific replication and antitumor efficacy. However, although generally the oncolytic efficacy of these approaches has been demonstrated in preclinical studies the therapeutic efficacy in clinical trails is still not optimal. Therefore, strategies are evaluated that could further enhance the oncolytic potential of conditionally replicating viruses. In this respect, the use of tumor-selective viruses in conjunction with other standard therapies seems most promising. However, still several hurdles regarding clinical limitations and safety issues should be overcome before this mode of therapy can become of clinical relevance.

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Section: Viral Dependency On Tissue/tumor-specific Promotersmentioning

confidence: 99%

Replication-selective oncolytic viruses in the treatment of cancer

2004

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“…Both plasmids were transfected into Ad293 cells by the use of Lipofectamine 2000 (Invitrogen). Ad-enhanced green fluorescent protein (EGFP) (an E1 deleted replication-deficient adenovirus with EGFP expression cassette), Ad-null (an E1 deleted replicationdeficient adenovirus without any exogenous gene), Ad-TERT-E1A/E1B (a replication-competent adenovirus with telomerase reverse transcriptase promoter-driven E1A/E1B expression cassette) 25 and dl309 (an adenoviral mutant with intact E1) were made or maintained earlier in our laboratory.…”

Section: Construction Package and Preparation Of Adenovirusmentioning

confidence: 99%

Novel strategies to augment genetically delivered immunotoxin molecular therapy for cancer therapy

Liu

Zhang

et al. 2009

Cancer Gene Ther

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Immunotoxin therapy is a promising molecular cancer treatment strategy. Its main advantage is seletive cytotoxicity towards tumor cells and minimal toxicity in normal tissues. However, a short half-life and rapid clearance severely hampers its clinical application. We report here a novel genetic approach in which a recombinant adenovirus vector was used to deliver an immunotoxin gene e23(scFv)-PE40 targeted to the oncogene c-erbB-2 (also known as Her2/neu). This vector, when combined with a low dose of a conditionally replicative adenovirus vector (CRAd), has enhanced tumor-killing ability either alone or in combination with the chemotherapeutic agent etoposide. Our data show that low-dose CRAd facilitated the replication of replication-deficient Ade23(scFv)-PE40 up to 6-20 times and the transcription of e23(scFv)-PE40 gene up to 12 times. Moreover, etoposide increased the e23(scFv)-PE40 transcription up to 8.5 times. Furthermore, we show that systemic application of Ad-e23(scFv)-PE40 and enhanced expression of the immunotoxin gene was well tolerated as determined by serum biochemical markers and histological examination of most vital organs. Taken together, our data support a novel genetic immunotoxin delivery approach that may yield enhanced efficacy against a variety of Her2/neu-expressing tumors.

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“…Normal adult tissues, with few exceptions, do not express this protein (14). Telomerase is also targeted because of the critical role it plays in tumor development and survival (13,(15)(16)(17)(18)(19)(20). The therapeutic strategies under investigation include functional inhibition by genetic and pharmacologic approaches (15,16,18,19) as well as immunotherapy (20).…”

Section: Introductionmentioning

confidence: 99%

Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

Dupont

Latouche

et al. 2005

Cancer Research

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Human telomerase reverse transcriptase (hTERT) is overexpressed in most human tumors, making it a potential target for cancer immunotherapy. hTERT-derived CTL epitopes have been identified previously, including p865 (RLVDDFLLV) and p540 (ILAKFLHWL), which are restricted by the human leukocyte antigen (HLA) class I A*0201 allele. However, it remains a major challenge to efficiently and consistently expand hTERT-specific CTLs from donor peripheral blood T lymphocytes. To bypass the need for generating conventional antigen-presenting cells (APCs) on an autologous basis, we investigated the potential ability of fibroblast-derived artificial APCs (AAPCs) to activate and expand HLA-A*0201-restricted CTLs. We show here that AAPCs stably expressing HLA-A*0201, human B 2 -microglobulin, B7.1, intercellular adhesion molecule-1, and LFA-3, together with either p540 and p865 minigenes or the full-length hTERT, effectively stimulate tumoricidal, hTERT-specific CTLs. hTERT-expressing AAPCs stimulated both p540 and p865 CTLs as shown by peptide-specific cytolysis and tetramer staining, indicating that hTERT is processed by the AAPCs and that the two peptides are presented as codominant epitopes. The level of cytotoxic activity against a panel of tumors comprising hematologic and epithelial malignancies varied, correlating overall with the level of HLA-A2 and hTERT expression by the target cell. Starting from 100 mL blood, f100 million hTERTspecific CTLs could be generated over the course of five sequential stimulations, representing an expansion of f1 Â 10 5 . Our data show that AAPCs process hTERT antigen and efficiently stimulate hTERT-specific CTLs from human peripheral blood T lymphocytes and suggest that sufficient expansion could be achieved to be clinically useful for adoptive cell therapy. (Cancer Res 2005; 65(12): 5417-27)

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A Novel Conditionally Replicative Adenovirus Vector Targeting Telomerase-Positive Tumor Cells

Cited by 53 publications

References 22 publications

Replication-selective oncolytic viruses in the treatment of cancer

Replication-selective oncolytic viruses in the treatment of cancer

Novel strategies to augment genetically delivered immunotoxin molecular therapy for cancer therapy

Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

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