Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors

V W van Beusechem, D C J Mastenbroek, P B van den Doel, M L M Lamfers, Jacques Grill, T Würdinger, H J Haisma, H M Pinedo, W R Gerritsen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Conditionally replicative adenoviruses (CRAds) are potentially useful agents for anticancer virotherapy approaches. However, lack of coxsackievirus and adenovirus receptor (CAR) expression on many primary tumor cells limits the oncolytic potency of CRAds. This makes the concept of targeting, that is, redirecting infection via CAR-independent entry pathways, relevant for CRAd development. Bispecific adapter molecules constitute highly versatile means for adenovirus targeting. Here, we constructed a CRAd with the Delta24 E1A mutation that produces a bispecific single-chain antibody directed towards the adenovirus fiber knob and the epidermal growth factor receptor (EGFR). This EGFR-targeted CRAd exhibited increased infection efficiency and oncolytic replication on CAR-deficient cancer cells and augmented lateral spread in CAR-deficient 3-D tumor spheroids in vitro. When compared to its parent control with native tropism, the new CRAd exhibited similar cytotoxicity on CAR-positive cancer cells, but up to 1000-fold enhanced oncolytic potency on CAR-deficient, EGFR-positive cancer cells. In addition, EGFR-targeted CRAd killed primary human CAR-deficient brain tumor specimens that were refractory to the parent control virus. We conclude, therefore, that CRAds expressing bispecific targeting adapter molecules are promising agents for cancer treatment. Their use is likely to result in enhanced oncolytic replication in cancerous tissues and thus in more effective tumor regression.

Original languageEnglish
Pages (from-to)1982-91
Number of pages10
JournalGene Therapy
Volume10
Issue number23
DOIs
Publication statusPublished - Nov 2003

Cite this

van Beusechem, V W ; Mastenbroek, D C J ; van den Doel, P B ; Lamfers, M L M ; Grill, Jacques ; Würdinger, T ; Haisma, H J ; Pinedo, H M ; Gerritsen, W R. / Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. In: Gene Therapy. 2003 ; Vol. 10, No. 23. pp. 1982-91.
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abstract = "Conditionally replicative adenoviruses (CRAds) are potentially useful agents for anticancer virotherapy approaches. However, lack of coxsackievirus and adenovirus receptor (CAR) expression on many primary tumor cells limits the oncolytic potency of CRAds. This makes the concept of targeting, that is, redirecting infection via CAR-independent entry pathways, relevant for CRAd development. Bispecific adapter molecules constitute highly versatile means for adenovirus targeting. Here, we constructed a CRAd with the Delta24 E1A mutation that produces a bispecific single-chain antibody directed towards the adenovirus fiber knob and the epidermal growth factor receptor (EGFR). This EGFR-targeted CRAd exhibited increased infection efficiency and oncolytic replication on CAR-deficient cancer cells and augmented lateral spread in CAR-deficient 3-D tumor spheroids in vitro. When compared to its parent control with native tropism, the new CRAd exhibited similar cytotoxicity on CAR-positive cancer cells, but up to 1000-fold enhanced oncolytic potency on CAR-deficient, EGFR-positive cancer cells. In addition, EGFR-targeted CRAd killed primary human CAR-deficient brain tumor specimens that were refractory to the parent control virus. We conclude, therefore, that CRAds expressing bispecific targeting adapter molecules are promising agents for cancer treatment. Their use is likely to result in enhanced oncolytic replication in cancerous tissues and thus in more effective tumor regression.",
keywords = "Adenovirus E1A Proteins/genetics, Animals, Cell Line, Tumor, Coxsackie and Adenovirus Receptor-Like Membrane Protein, Gene Targeting, Genetic Therapy/methods, Genetic Vectors/genetics, Humans, Immunoglobulin Fc Fragments/immunology, Neoplasms/immunology, Receptor, Epidermal Growth Factor/immunology, Receptors, Virus/deficiency, Virus Replication",
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Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. / van Beusechem, V W; Mastenbroek, D C J; van den Doel, P B; Lamfers, M L M; Grill, Jacques; Würdinger, T; Haisma, H J; Pinedo, H M; Gerritsen, W R.

In: Gene Therapy, Vol. 10, No. 23, 11.2003, p. 1982-91.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors

AU - van Beusechem, V W

AU - Mastenbroek, D C J

AU - van den Doel, P B

AU - Lamfers, M L M

AU - Grill, Jacques

AU - Würdinger, T

AU - Haisma, H J

AU - Pinedo, H M

AU - Gerritsen, W R

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N2 - Conditionally replicative adenoviruses (CRAds) are potentially useful agents for anticancer virotherapy approaches. However, lack of coxsackievirus and adenovirus receptor (CAR) expression on many primary tumor cells limits the oncolytic potency of CRAds. This makes the concept of targeting, that is, redirecting infection via CAR-independent entry pathways, relevant for CRAd development. Bispecific adapter molecules constitute highly versatile means for adenovirus targeting. Here, we constructed a CRAd with the Delta24 E1A mutation that produces a bispecific single-chain antibody directed towards the adenovirus fiber knob and the epidermal growth factor receptor (EGFR). This EGFR-targeted CRAd exhibited increased infection efficiency and oncolytic replication on CAR-deficient cancer cells and augmented lateral spread in CAR-deficient 3-D tumor spheroids in vitro. When compared to its parent control with native tropism, the new CRAd exhibited similar cytotoxicity on CAR-positive cancer cells, but up to 1000-fold enhanced oncolytic potency on CAR-deficient, EGFR-positive cancer cells. In addition, EGFR-targeted CRAd killed primary human CAR-deficient brain tumor specimens that were refractory to the parent control virus. We conclude, therefore, that CRAds expressing bispecific targeting adapter molecules are promising agents for cancer treatment. Their use is likely to result in enhanced oncolytic replication in cancerous tissues and thus in more effective tumor regression.

AB - Conditionally replicative adenoviruses (CRAds) are potentially useful agents for anticancer virotherapy approaches. However, lack of coxsackievirus and adenovirus receptor (CAR) expression on many primary tumor cells limits the oncolytic potency of CRAds. This makes the concept of targeting, that is, redirecting infection via CAR-independent entry pathways, relevant for CRAd development. Bispecific adapter molecules constitute highly versatile means for adenovirus targeting. Here, we constructed a CRAd with the Delta24 E1A mutation that produces a bispecific single-chain antibody directed towards the adenovirus fiber knob and the epidermal growth factor receptor (EGFR). This EGFR-targeted CRAd exhibited increased infection efficiency and oncolytic replication on CAR-deficient cancer cells and augmented lateral spread in CAR-deficient 3-D tumor spheroids in vitro. When compared to its parent control with native tropism, the new CRAd exhibited similar cytotoxicity on CAR-positive cancer cells, but up to 1000-fold enhanced oncolytic potency on CAR-deficient, EGFR-positive cancer cells. In addition, EGFR-targeted CRAd killed primary human CAR-deficient brain tumor specimens that were refractory to the parent control virus. We conclude, therefore, that CRAds expressing bispecific targeting adapter molecules are promising agents for cancer treatment. Their use is likely to result in enhanced oncolytic replication in cancerous tissues and thus in more effective tumor regression.

KW - Adenovirus E1A Proteins/genetics

KW - Animals

KW - Cell Line, Tumor

KW - Coxsackie and Adenovirus Receptor-Like Membrane Protein

KW - Gene Targeting

KW - Genetic Therapy/methods

KW - Genetic Vectors/genetics

KW - Humans

KW - Immunoglobulin Fc Fragments/immunology

KW - Neoplasms/immunology

KW - Receptor, Epidermal Growth Factor/immunology

KW - Receptors, Virus/deficiency

KW - Virus Replication

U2 - 10.1038/sj.gt.3302103

DO - 10.1038/sj.gt.3302103

M3 - Article

VL - 10

SP - 1982

EP - 1991

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 23

ER -