Development of new adenoviral vectors for the treatment of gastrointestinal cancers.

The laboratory is focused in the development of new treatments for liver cancer based on gene therapy. So far, most gene threrapy approaches applied to cancer have demonstrated a good safety profile, but efficacy is still very low. Some of the reasons include inefficient gene transfer and short duration of therapeutic gene expression. In order to overcome these limitations, we have started two different approaches:

1. Combination of the direct antitumor effect of oncolytic adenoviruses plus the expression of immunostimulatory genes such as interleukin-12 (IL-12). The goal is to stimulate an immune response against cancer cells, to achieve a systemic response that will attack the primary tumor and distant metastases. Oncolytic viruses are designed to infect, replicate and kill preferentially cancer cells. When these viruses reach the target cells, they complete their viral cycle and cause cell death and liberation of thousands of newly formed viruses that are able to infect other cells in the tumor. In addition, when oncolytic adenoviruses are adapted as gene therapy vectors, they amplify the expression of the therapeutic gene. This way, we plan to achieve an enhanced immune response against the tumor, because we can get higher IL-12 expression in the context of the imflammation and cell destruction caused by the virus.

2. Use of a High-Capacity adenoviral vector (HC-Ad) for the controlled expression of IL-12. The advantage of these vectors is that they lack all viral genes. Therefore, they are less immunogenic and allow expression of the transgene for extended periods of time. In addition, they can accomodate large segments of genetic material. In colaboration with other groups, we took advantage of these characteristics and developed a HC-Ad carrying an inducible expression system for IL-12. In this way, we can modulate the time and intensity of IL-12 expression. This is important because IL-12 can cause severe toxicity at high doses. Now we are optimizing the treatment protocols in order to achieve the maximum antitumor effect with reduced toxicity.