Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM

Haisma, Hidde J.; Pinedo, H.M.; Rijswijk, A. Van; Meulen-Muileman, I. Van Der; Sosnowski, Barbara A.; Ying, Wenbin; Beusechem, Victor W. van; Tillman, Bryan; Gerritsen, Winald R.; Curiel, David T.

doi:10.1038/sj.gt.3300969

Cited by 94 publications

(54 citation statements)

References 14 publications

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“…The trifunctional antibody catumaxomab (anti-Ep-CAM Â anti-CD3) has been safely administered in a phase I/II study to patients suffering from malignant ascites (Stroehlein et al, 2005). Bispecific antibodies that link adenovirus to Ep-CAM are experimentally used in combination with recombinant adenoviral vectors for cancer gene therapy (Haisma et al, 1999), and adenoviral vectors expressing virus with an anti-Ep-CAM surface protein were also constructed (Oosterhoff et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers

et al. 2006

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Epithelial cell adhesion molecule (Ep-CAM; CD326) is used as a target by many immunotherapeutic approaches, but little data are available about Ep-CAM expression in major human malignancies with respect to level, frequency, tumour stage, grade, histologic tumour type and impact on survival. We analysed by immunohistochemical staining tissue microarrays with 4046 primary human carcinoma samples from colon, stomach, prostate and lung cancers for both frequency and intensity of Ep-CAM expression under highly standardised conditions. A total of 3360 samples were analysable. High-level Ep-CAM expression was observed in 97.7% (n ¼ 1186) of colon, 90.7% of gastric (n ¼ 473), and 87.2% of prostate cancers (n ¼ 414), and in 63.9% of lung cancers (n ¼ 1287). No detectable Ep-CAM staining was found with only 0.4% of colon, 2.5% of gastric, 1.9% of prostate cancers, and 13.5% of lung cancers. The only significant correlation of Ep-CAM expression with tumour grading was observed in colon cancer where high-level Ep-CAM expression on grade 3 tumours was down to 92.1% (Po0.0001). Adenosquamous and squamous carcinomas of the lung had a lower percentage of high-level Ep-CAM expression compared to adenocarcinomas with 35.4 and 53.6%, respectively, and with 45.5 and 17.3% of tumours being Ep-CAM negative. With the exception of moderately differentiated colon carcinoma, where patients not expressing Ep-CAM on their tumours showed an inferior survival (P ¼ 0.0014), correlation of Ep-CAM expression with survival did not reach statistical significance for any of the other cancer indications and subgroups. In conclusion, the data strongly support the notion that Ep-CAM is a prime target for immunotherapies in major human malignancies. This is because the most common human cancers show (i) a low frequency of Ep-CAM-negative tumours, (ii) a high frequency of Ep-CAM expression on cells of a given tumour, and (iii) for most cancers, an insignificant influence of tumour staging, grading and histology on Ep-CAM expression.

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Section: Discussionmentioning

confidence: 99%

Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers

et al. 2006

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“…Single cell suspensions were prepared by repetitive incubation with Liver Digest Medium ( Life Technologies, Breda, the Netherlands ) essentially as described before. 17 AdCMVluc is an E1 /E3 -deleted replication-deficient Ad5 vector, which expresses firefly luciferase under the control of the immediate -early cytomegalovirus (CMV ) promoter that was obtained from R.D. Gerard ( University of Texas Southwestern Medical Center, Dallas, TX ).…”

Section: Cells Viruses Antibodies and Conjugatementioning

confidence: 99%

“…21 Bispecific conjugate of 1D6.14 Fab H and 323 /A3 Fab H was produced by chemical linkage as previously described. 17 …”

Section: Cells Viruses Antibodies and Conjugatementioning

confidence: 99%

“…9,13 ± 16 Targeting of adenoviral vectors toward tumor cells via EpCAM can be achieved by utilizing a bispecific immunoconjugate consisting of the Fab H domains of a neutralizing antibody against the adenovirus fiber -knob ( binding domain for CAR ) and an anti -EpCAM antibody. 17 The function of this conjugate is 2-fold: ( a) it blocks the natural binding of adenovirus to CAR present on many different cell types, and ( b) it directs the adenovirus to EpCAM-expressing cells.…”

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Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors

et al. 2001

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Application of recombinant adenoviral vectors for cancer gene therapy is currently limited due to lack of specificity for tumor cells. For gastric and esophageal adenocarcinoma, we present here that the relative abundant expression of the primary adenovirus receptor, coxsackie / adenovirus receptor ( CAR ), on normal epithelium compared to carcinoma favors the transduction of the epithelium. As such, to achieve specific transduction of cancer cells, targeting approaches are required that ablate the binding of the virus to CAR and redirect the virus to tumor -specific receptors. By immunohistochemistry and reverse transcriptase polymerase chain reaction assays, we demonstrate a marked difference in expression of the human epithelial cell adhesion molecule ( EpCAM ) between normal and ( pre )malignant lesions of the stomach and esophagus. Based on this, we explored the feasibility of using EpCAM to achieve gastric and esophageal adenocarcinoma selective gene transfer. Adenoviral vectors redirected to EpCAM using bispecific antibodies against the adenovirus fiber -knob protein and EpCAM specifically infected gastric and esophageal cancer cell lines. Using primary human cells, an improved ratio of tumor transduction over normal epithelium transduction was accomplished by the EpCAM -targeted vectors. This study thus indicates that EpCAM -targeted adenoviral vectors may be useful for gastric and esophageal cancer ± specific gene therapy in patients. Cancer Gene Therapy ( 2001 ) 8, 342 ± 351

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“…52 Other Fab-ligand conjugates targeted against Ep-CAM, Tag-72, epidermal growth factor (EGF) receptor, CD-40 and other cell markers have been employed in a similar manner with promising results. 1,[53][54][55][56][57][58] Dmitriev et al 60 developed an elegant alternative to the chemical conjugate approach by creating a single recombinant fusion molecule formed by a truncated, soluble form of CAR (sCAR) fused to either an anti-CD40 antibody 59 or epidermal growth factor (EGF). Using the latter, a nine-fold increase in reporter gene expression was achieved in several EGFR-overexpressing cancer cell lines compared to untargeted Ad or EGFR-negative cells in vitro.…”

Section: Adapter-based Ad Targetingmentioning

confidence: 99%

Transductional targeting of adenovirus vectors for gene therapy

2006

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Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM

Cited by 94 publications

References 14 publications

Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers

Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors

Transductional targeting of adenovirus vectors for gene therapy

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