Adenovirus Tumor Targeting and Hepatic Untargeting by a Coxsackie/Adenovirus Receptor Ectodomain Anti–Carcinoembryonic Antigen Bispecific Adapter

Li, Hua‐Jung; Everts, Maaike; Pereboeva, Larisa; Komarova, Svetlana V.; Idan, Anat; Curiel, David T.; Herschman, Harvey R.

doi:10.1158/0008-5472.can-06-4679

Cited by 40 publications

(45 citation statements)

References 23 publications

(31 reference statements)

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“…Our observations are consistent with previous reports showing that the use of adapters containing the CAR ectodomain led to reduced hepatic uptake of adenoviral vectors after systemic delivery, which is an important aspect for future application of adenoviral vectors in the clinic (15,16,33). Using the oncolytic adenovirus hTERT-Ad, which may cause liver damage after systemic high-dose administration, we showed that hepatotoxicity was prevented by CARscpSia pretreatment.…”

Section: Discussionsupporting

confidence: 92%

“…2C) and confirmed the significant decrease of adenoviral liver load when adenovirus was pretreated with CARsc-pSia. These results demonstrate successful inhibition of adenoviral hepatotropism by CARsc-pSia and support previous reports in which CAR ectodomain containing adapters with alternative tumor-binding moieties were used (15,16,33). To evaluate whether CARsc-pSiadependent hepatic detargeting can prevent toxicity in vivo, we infected mice with repeated high-dose applications of an oncolytic adenovirus with or without CARsc-pSia pretreatment.…”

Section: Carsc-psia-mediated Hepatic Detargeting Of Adenovirus Reducesupporting

confidence: 85%

“…In our study, we have developed an adapterbased strategy to redirect oncolytic adenovirus infection to tumors, which express polySia, an excellent molecular target on the cell surface of clinically relevant tumors. For this purpose, we adapted the concept of bispecific adapters that has already been used for retargeting of adenoviral vectors to tumor-enriched structures such as Her2-Neu, EGFR, or CEA (12,13,15). As targeting ligand, we generated a polySiabinding scFv to establish the bispecific adapter CARsc-pSia.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, binding of factor X to adenoviral hexon has been identified to mediate liver uptake (14). Nevertheless, bispecific adapters containing the CAR-ectodomain reduce adenoviral liver load, suggesting that fiberknob is involved in adenoviral hepatotropism (15,16).…”

Section: Introductionmentioning

confidence: 99%

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PolySia-Specific Retargeting of Oncolytic Viruses Triggers Tumor-Specific Immune Responses and Facilitates Therapy of Disseminated Lung Cancer

Kloos

Woller

Gürlevik

et al. 2015

Cancer Immunology Research

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Polysialic acid (polySia) is expressed on several malignant tumors of neuroendocrine origin, including small cell lung cancer. In this study, we investigated the therapeutic efficacy of tumor-directed T-cell responses, elicited by polySia-retargeted oncolytic adenovirus infection, in an orthotopic murine model of disseminated polySia-positive lung cancer. In several cell lines, we demonstrated highly polySia-selective retargeting of adenoviral infection using a bispecific adapter comprising the ectodomain of the coxsackievirus/adenovirus receptor and a polySia-recognizing single-chain antibody domain. PolySiadependent systemic infection in vivo facilitated effective uptake of viruses in subcutaneous polySia-expressing human tumors, whereas hepatic viral load and hepatotoxicity were significantly reduced. The impact and nature of antitumoral immune responses triggered by systemic delivery of polySia-retargeted oncolytic adenoviruses were investigated in an orthotopic model of disseminated lung cancer. Interestingly, improved transduction by polySia-retargeted oncolytic adenoviruses led to CD45-positive cell infiltrates in close association with large lytic areas. Consistently, enhanced tumor regression and prolonged survival was only observed in immunocompetent mice, but not in T-celldeficient mice. To investigate whether improved systemic infection by polySia retargeting would elicit a tumor-specific T-cell response, we screened the used lung cancer cells for mutated oncogenes by complete exon sequencing. In agreement with our other results, only retargeted oncolysis was able to induce a significant response specific for the tumor-associated neoepitope Gsta2-Y9H. In conclusion, we demonstrated that effective retargeting of oncolytic adenovirus against polySia-expressing tumors elicits an effective tumor-directed T-cell response after systemic virus delivery and facilitates therapy of disseminated lung cancer.

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Section: Discussionsupporting

confidence: 92%

Section: Carsc-psia-mediated Hepatic Detargeting Of Adenovirus Reducesupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PolySia-Specific Retargeting of Oncolytic Viruses Triggers Tumor-Specific Immune Responses and Facilitates Therapy of Disseminated Lung Cancer

Kloos

Woller

Gürlevik

et al. 2015

Cancer Immunology Research

View full text Add to dashboard Cite

show abstract

“…colon, lung and breast, it was possible to target vectors by using a bi-specific adapter protein, which fused the ectodomain of CAR with a single-chain anti-carcinoembryonic antigen (CEA) antibody. This adaptor molecule allowed the targeting of AdV vectors to CEA-positive epithelial tumor cells in cell culture, in subcutaneous tumor grafts, and in hepatic tumor grafts (Li et al, 2007). A similar strategy was used for vector targeting to pancreatic carcinoma cells by using a vector bearing an EGF peptide fused with CAR (Wesseling et al, 2001).…”

Section: Molecular Adaptors For Adv Targetingmentioning

confidence: 99%