Cloning and characterization of an adenoviral vector for highly efficient and doxycycline – suppressible expression of bioactive human single – chain interleukin 12 in colon cancer

Abstract

Background: Interleukin-12 (IL-12) is well characterized to induce cellular antitumoral immunity by activation of NK-cells and T-lymphocytes. However, systemic administration of recombinant human IL-12 resulted in severe toxicity without perceptible therapeutic benefit. Even though intratumoral expression of IL-12 leads to tumor regression and long-term survival in a variety of animal models, clinical trials have not yet shown a significant therapeutic benefit. One major obstacle in the treatment with IL-12 is to overcome the relatively low expression of the therapeutic gene without compromising the safety of such an approach. Our objective was to generate an adenoviral vector system enabling the regulated expression of very high levels of bioactive, human IL-12.

Tumor-associated immune factors are associated with recurrence and metastasis in non-small cell lung cancer

“… 18 Soluble cytokines also found in the tumor microenvironment include IL-10, TGF-β, VEGF and PGE2. 19 , 20 , 21 Indoleamine 2,3-dioxygenase and arginase I (refs 22 , 23 ) are metabolic factors found deregulated in microenvironment, whereas those of immune inhibitory ligands include B7-H4 and PD-1. 24 , 25 A variety of factors regulate the tumor inhibitory network in the microenvironment.…”

Turning the gene tap off; implications of regulating gene expression for cancer therapeutics

“…Although the Tet-Off system has been criticized because it exhibits 1% to 10% leakage in the ''off'' state (12), it still allows to substantially reduce transgene expression when side effects arise. For instance, the severe side effects associated to the systemic administration of interleukins (IL) for the treatment of colon cancer led to the construction of adenoviral vectors expressing IL-12 driven by the Tet-Off system, which yields high levels of IL-12 that are inhibited 99% in the presence of doxycycline (14). Retroviruses encoding the Tet-Off system also produce high levels of thymidine kinase, with <0.5% basal expression in the ''off'' state (15).…”