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Fiber Knob Modifications Overcome Low, Heterogeneous Expression of the Coxsackievirus-Adenovirus Receptor That Limits Adenovirus Gene Transfer and Oncolysis for Human Rhabdomyosarcoma Cells¹

Division of Hematology/Oncology [T. P. C., N. H. V., Y. Y. M., M. A. C.] and Department of Pathology [M. H. C., J. D. S.], Children’s Hospital Medical Center, Cincinnati, Ohio 45229; Division of Pediatric Hematology/Oncology, University of Wisconsin Children’s Hospital and Comprehensive Cancer Center, Madison, Wisconsin 53792 [E. J. D., A. D. H., A. S.]; University of Alabama, Birmingham, Alabama 35294 [V. K., D. T. C.]; Research and Development, GenVec Inc., Gaithersburg, Maryland 20879 [T. J. W.]; University of Colorado Health Sciences Center, Denver, Colorado 80262 [J. D.]; and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 [J. M. B.]

Exploiting the lytic life cycle of viruses has gained recent attention as an anticancer strategy (oncolysis). To explore the utility of adenovirus (Ad)-mediated oncolysis for rhabdomyosarcoma (RMS), we tested RMS cell lines for Ad gene transduction and infection. RMS cells were variably transduced by Ad. Compared with control cells, RMS cells were less sensitive or even resistant to oncolysis by wild-type virus. RMS cells expressed the Ad internalization receptors, _v integrins, but had low or undetectable expression of the major attachment receptor, coxsackievirus-Ad receptor (CAR). Mutant Ads with ablated CAR binding exhibited only 5–20% of transgene expression in RMS cells seen with a wild-type vector, suggesting that residual or heterogeneous CAR expression mediated the little transduction that was detectable. Immunohistochemical analysis of archived clinical specimens showed little detectable CAR expression in five embryonal and eight alveolar RMS tumors. Stable transduction of the cDNA for CAR enabled both efficient Ad gene transfer and oncolysis for otherwise resistant RMS cells, suggesting that poor CAR expression is the limiting feature. Gene transfer to RMS cells was increased >2 logs using Ads engineered with modified fiber knobs containing either an integrin-binding RGD peptide or a polylysine peptide in the exposed HI loop. The RGD modification enabled increased oncolysis for RMS cells by a conditionally replicative Ad, Ad24RGD, harboring a retinoblastoma-binding mutation in the E1A gene. Thus, the development of replication-competent vectors targeted to cell surface receptors other than CAR is critical to advance the use of Ad for treating RMS.

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