Development of high capacity adenovirus vectors with different therapeutical approaches for cancer treatment

Abstract

The use of high-capacity adenovirus vectors in cancer therapy has been promising. These vectors are considered safer and with higher cloning capacity in comparison to first and second generations adenovirus vectors. Different approaches can be explored while using adenoviruses as gene carriers, such as inducing the expression of antitumor genes or deleting pro-tumor genes, both leading to the destruction of cancer cells. The expression of herpes simplex virus thymidine kinase gene in cancer cells, for example, promotes cell death in combination with the drug ganciclovir. Also, an optimized version of interleukin-12 presents antitumor activity and has higher immunomodulatory capacity in comparison to regular IL-12. On the other hand, the toll-like receptor 4 (TLR4) is found expressed in head and neck tumor cells. Through activation, TLR4 leads to pro-tumor effects and its inactivation is related to proliferation and migration inhibition, showing that TLR4 must be an interesting therapeutic target for head and neck cancer. In this project, we aim to develop and evaluate the antitumor activity of two high capacity adenovirus vectors, the PUC-Ad12-TCPtkevIL12 vector, expressing HSVtk and optimized IL-12 under control of calcitonin promoter in medullary thyroid carcinoma; and the PUC-Ad12-TLR4KO vector, carrying CRISPR/Cas9 with guide RNAs for TLR4 silencing under control of p16INK4A promoter, in HPV positives head and neck tumors. (AU)