Construction and evaluation of conditionally Replication-Competent adenoviral vectors expressing interleukins and interleukin receptors for in vivo Reduction/Erradication of B16F10-Nex2 mice tumoral cells in C57BL/6 mice

Abstract

Melanoma is an important public-health issue because of high prevalence and constant increase in Caucasian populations. The development of malignant melanoma is assumed to be a multistep complex process, acquiring metastatic potential with increasing thickness, being metastatic melanoma fatal and resistant to conventional therapies. These observations underscore the need for improved treatment modalities that target the metastatic component of this disease, as gene-based therapy employing tumor suppressor gene In that way, diverse gene-based therapy approaches have been employed, as the development of vaccines based on the use of recombinant proteins and DNA vaccines carrying genes coding for antigens expressed at high levels by melanoma cells, or the administration of genes coding for pro-inflammatory cytokines or for immunosuppressor compounds inhibitors, by DNA plasmids and viral vector approaches. These DNA vaccines lead to anti-tumor immune responses, however they elicited autoimmune responses also. The most successful approach developed until this moment, aiming the eradication of metastatic melanoma, is the one based on conditionally replication competent adenoviruses or CRCAs. Injecting Ad.PEG-E1A-mda-7 CTV into xenografts derived from MeWo human metastatic melanoma cells in athymic nude mice completely eliminated not only primary treated tumors but also distant non-treated tumors. Mda-7/IL-24 was expressed only by tumoral cells, having limited activity on normal cells. This is an extremely desirable characteristic for the anti-tumor gene-based therapy. Based on these successful results achieved by the use of CRCAs expressing pro-inflammatory cytokines and immunosuppressor compounds inhibitors, this project purposes the construction CRCAs based on the use of the PEG-Prom to drive expression of the E1A gene, necessary for Ad replication, to create cancer-cell-specific CRCAs expressing the IL12 interleukin and the receptors for IL10 e IL13 in the E3 region, aiming the development of an efficient anti-tumor gene-based therapy to treat melanoma e metastatic melanoma. (AU)