Clinical data from cancer patients treated with triple modified oncolytic adenovirus Ad5/3-Cox2L-D24

Background: Oncolytic adenoviruses are a promising experimental approach for treatment of cancers refractory to currently available modalities. A serotype chimeric virus selective for cyclooxygenase 2 (cox-2) overexpressing and Rb/p16 pathway mutant cells was constructed and and tested preclinically. Subsequently, patients progressing after routine anti-cancer treatments were treated with Ad5/3-Cox2L-D24 in a compassionate use scheme. Methods: 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. Results: Following promising preclinical efficacy, safety and biodistribution data (Baeurschmitz Mol Ther 2006), treatment of patients with tumors refractory to all available modalities was initiated. By abstract submission, 21 patients with NSCLC, hepatocellular, small intestinal, colon, breast, ovarian, pancreatic, gastric cancer or malignant fibrous histiosarcoma have been safely treated intra-tumorally, intraperitoneally and intravenously. Treatments have been well tolerated and there is evidence of efficacy in a significant proportion of patients. Complete data, including Cox2 analysis of tumors, imaging, hema-tological, immunological and safety analysis will be presented at the meeting. Conclusion: Ad5/3-Cox2L-D24 is a promising agent for treatment of Cox-2 expressing tumors refractory to available modalities and represents the first non-CAR binding oncolytic adenovirus used in humans. These preliminary "phase 0" data set the stage for clinical trials.