Local gene therapy of solid tumors with GM-CSF and B7-1 eradicates both treated and distal tumors

Collins, Christopher G.; Tangney, Mark; Larkin, John; Casey, Garrett; Whelan, Maria; Cashman, James; Murphy, John; Soden, Declan M.; Vejda, Susanne; McKenna, Sharon L.; Kiely, Barry; Collins, John; Barrett, John; Aarons, Simon; O’Sullivan, G.

doi:10.1038/sj.cgt.7700976

Cited by 37 publications

(46 citation statements)

References 21 publications

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“…[6][7][8][9][10][11][12][13][14][15] Moreover, studies on different tumor types using the same delivery system have shown different transfection efficiencies. [6][7][8][9][10] There is a substantial amount of literature explaining variable transfection efficiencies in vitro as well as in vivo due to variations in optimal experimental conditions, therapeutic genes, plasmid DNA backbone and mice age, [16][17][18] whereas the results of only a few studies performed on tumors in vivo and on tumor spheroids have drawn attention to tumor microenvironment and to the problems related to transport of DNA through the tumor tissue.…”

Section: Introductionmentioning

confidence: 99%

The effect of the histological properties of tumors on transfection efficiency of electrically assisted gene delivery to solid tumors in mice

et al. 2007

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Uniform DNA distribution in tumors is a prerequisite step for high transfection efficiency in solid tumors. To improve the transfection efficiency of electrically assisted gene delivery to solid tumors in vivo, we explored how tumor histological properties affected transfection efficiency. In four different tumor types (B16F1, EAT, SA-1 and LPB), proteoglycan and collagen content was morphometrically analyzed, and cell size and cell density were determined in paraffin-embedded tumor sections under a transmission microscope. To demonstrate the influence of the histological properties of solid tumors on electrically assisted gene delivery, the correlation between histological properties and transfection efficiency with regard to the time interval between DNA injection and electroporation was determined. Our data demonstrate that soft tumors with larger spherical cells, low proteoglycan and collagen content, and low cell density are more effectively transfected (B16F1 and EAT) than rigid tumors with high proteoglycan and collagen content, small spindle-shaped cells and high cell density (LPB and SA-1). Furthermore, an optimal time interval for increased transfection exists only in soft tumors, this being in the range of 5-15 min. Therefore, knowledge about the histology of tumors is important in planning electrogene therapy with respect to the time interval between DNA injection and electroporation.

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Section: Introductionmentioning

confidence: 99%

The effect of the histological properties of tumors on transfection efficiency of electrically assisted gene delivery to solid tumors in mice

et al. 2007

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“…GM-CSF and CD80 have definite function and have been widely used in cancer gene therapy. [37][38][39] Their therapeutic effect has been widely recognized, so we chose them as transgenes for our CRAD. The expression of GM-CSF and CD80 was greatly improved in tumor cells infected by Ad-CD80-TPE-GM, compared with cells infected by the control Ad (Figures 2b and c).…”

Section: Discussionmentioning

confidence: 99%

A simplified system for generating oncolytic adenovirus vector carrying one or two transgenes

Zb¹,

Wu²,

Wang³

et al. 2007

Cancer Gene Ther

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Oncolytic adenoviruses, also called conditionally replicating adenoviruses (CRADs), have been widely applied in cancer gene therapy. However, the construction of CRADs is still time-consuming. In this study, we attempted to establish a simplified method of generating CRADs based on AdEasy system. A novel plasmid pTE-TPE-GM was constructed, containing sequentially positioned promoter of telomerase reverse transcriptase (TERTp), coding sequence of E1A gene, promoter of E1B gene, granulocytemacrophage colony-stimulating factor (GM-CSF) gene, internal ribosome entry site sequence and coding sequence of E1B55K gene. The CRAD-generating system reported here include three plasmids: pTE-TPE-GM, pShuttle-CMV and AdEasy-1, one Escherichia coli strain BJ5183, and the packaging cell line 293. Using this system, an oncolytic adenovirus carrying B7-1 (CD80) and GM-CSF genes was successfully constructed and designated as Ad-CD80-TPE-GM. The expression of GM-CSF increased more than 9000 times in tumor cell lines infected by Ad-CD80-TPE-GM at a multiplicity of infection (MOI) of 5, compared with the cells infected by replication-defective control virus. Similarly, the expression of CD80 also increased 9-140 times. Ad-CD80-TPE-GM selectively replicates in TERT-positive tumor cells, and the progeny viruses can reach up to 375 infection units (IU) per cell. In vitro study showed that the Ad-CD80-TPE-GM induced an obvious oncolytic effect at MOI of 0.1, and killed about 80% TERT-positive tumor cells within 7 days at an MOI of 1. The antitumor effect of this vector was also investigated in Hep2 xenograft model of nude mice, and the tumor inhibition rate reached 74% at day 30 after the administration with a total dose of 1 Â 10 9 IU Ad-CD80-TPE-GM. Intratumoral injection of Ad-CD80-TPE-GM slightly induced neutralizing antibody against the oncolytic adenovirus in nude mice, which might contribute to the virus clearance in vivo. In conclusion, we successfully constructed an oncolytic CRAD carrying GM-CSF and CD80 gene. More importantly, this system can be modified to generate novel transcriptionally regulated CRADs with different tissue-specific promoters or transgenes.

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“…The JBS (murine fibrosarcoma) cell line was established and maintained as described earlier. 6 Induction of this tumour is not preventable by prior vaccination with cells in a diversity of protocols. 6 The C26 cell line was obtained from the ATCC and cultured in Dulbecco's Modified Eagle Medium (Sigma-Aldrich, Dublin, Ireland).…”

Section: Mice and Tumour Cell Linesmentioning

confidence: 99%

“…6 Induction of this tumour is not preventable by prior vaccination with cells in a diversity of protocols. 6 The C26 cell line was obtained from the ATCC and cultured in Dulbecco's Modified Eagle Medium (Sigma-Aldrich, Dublin, Ireland). Tumour induction in all experiments was by subcutaneous (s.c.) injection of 2 Â 10 6 JBS cells or 5 Â 10 4 C26 cells in 200 ml of serum-free Dulbecco's Modified Eagle Medium.…”

Section: Mice and Tumour Cell Linesmentioning

confidence: 99%

“…4,5 We have previously reported that a non-viral gene therapy, using a plasmid encoding the cytokine GM-CSF and the costimulatory molecule B7-1 delivered into a weakly immunogenic growing tumour in a mouse model resulted in the recruitment of effective cytotoxic anti-tumour responses and in the permanent elimination of 60% of established tumour masses. 6 These responses were tumour specific, durable and effective against a cancer, which was shown to be resistant to a diversity of preventive vaccination strategies.…”

Section: Introductionmentioning

confidence: 99%

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Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation

et al. 2010

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Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm 3 tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development.

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Local gene therapy of solid tumors with GM-CSF and B7-1 eradicates both treated and distal tumors

Cited by 37 publications

References 21 publications

The effect of the histological properties of tumors on transfection efficiency of electrically assisted gene delivery to solid tumors in mice

The effect of the histological properties of tumors on transfection efficiency of electrically assisted gene delivery to solid tumors in mice

A simplified system for generating oncolytic adenovirus vector carrying one or two transgenes

Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation

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