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• W2564960107 abstract "2818 Oncolytic adenoviruses are a promising experimental approach for treatment of cancers refractory to currently available modalities. The purpose of this study was to construct viruses selective for cyclooxygenase 2 (cox-2) overexpressing and Rb/p16 pathway mutant cells and test their utility in vitro, in animal models and in cancer patients. A 24 bp deletion (”D24”) was engineered in the constant region 2 of adenovirus E1A, which renders the virus unable to bind Rb. This interaction is necessary for induction of an S-phase like state needed for productive virus replication in normal cells. However, in tumor cells Rb/p16 pathway mutations are ubiquitous and therefore this interaction is not required. Further selectivity was achieved by replacing the native E1A promoter with the cox-2 promoter. High cox-2 expression is a hallmark of many types of aggressive carcinomas. The feasibility of combining D24 with the cox-2 promoter was confirmed in vitro and in orthotopic murine models of ovarian cancer. Adding D24 to the cox-2 promoter increased specificity without loss of efficacy. Adding the promoter to D24 reduced efficacy marginally but increased specificity significantly. Out of various combinations of promoter and deletion variants, Ad5/3-Cox2L-D24 emerged as the optimal construct with regard to efficacy and selectivity in vitro and in vivo. Because the coxsackie-adenovirus receptor CAR is variably expressed and frequently dysfunctional in many advanced tumors, we tested a number of approaches for increasing gene delivery to various types of advanced and aggressive tumors, including NSCLC, gastric, pancreatic, ovarian, cervical, SCCHN, colorectal, renal, breast and prostate cancer. While polylysine and RGD-4C modification of the adenoviral fiber knob were both effective for many tumor types, and far superior over CAR binding viruses, serotype chimerism with the Ad3 knob emerged as an approach with wide utility and is therefore featured in Ad5/3-Cox2L-D24. Following promising preclinical efficacy and safety data, treatment of patients with tumors refractory to all available modalities was initiated. By abstract submission, 4 patients with NSCLC, colon cancer, pancreatic cancer or malignant fibrous histiosarcoma have been safely treated intratumorally, intraperitoneally and intravenously. By the meeting, we expect to have treated half a dozen more. Efficacy and safety data will be presented. In summary, we propose that Ad5/3-Cox2L-D24 is a promising agent for treatment of cox-2 expressing tumors refractory to available modalities." @default.
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• W2564960107 date "2008-05-01" @default.
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• W2564960107 title "Treatment of cancer patients with capsid modified double controlled oncolytic adenovirus Ad5/3-Cox2L-D24" @default.
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