A team of researchers at IRCCS Ospedale San Raffaele described for the first time an innovative peri-operative immunotherapeutic approach with interferon-alpha that can prevent liver metastasis from primary colorectal cancer.

The preclinical study was coordinated by Giovanni Sitia, head of the Experimental Hepatology Unit, in collaboration with Luca Guidotti, deputy scientific director and Full Professor at the Vita-Salute San Raffaele University. The results were published in the scientific journal eLIFE, and the research was made possible by a grant from the AIRC Foundation for Cancer Research,

The anti-tumor activity of interferon alpha

Interferon alfa is a molecule normally produced by our body and has potent anti-tumor activity. Researchers administered low-dose interferon alfa to mouse models in the period just before and during surgery to remove colorectal cancer.

After delivery by this novel modality, the scientists observed that the drug was able to stimulate liver endothelial cells to build a vascular barrier. This, in turn, was able to limit the entry of cancer cells into the organ in question, thereby preventing metastasis formation.

Explains Giovanni Sitia, "This result is possible because of multiple mechanisms mediated by interferon-alpha. Initially it acts by building real physical barriers on the endothelial cells, which line the inside of the blood vessels, preemptively preventing colonization and metastatic growth. Subsequently, interferon alpha promotes the immune response against colorectal metastases, conferring long-term protection without causing apparent side effects."

Colorectal cancer and possible complications

Colorectal cancer is one of the highest incidence malignancies in the worldwide, and in Italy alone it ranks second in male and female populations in incidence and mortality. Screening campaigns and advances in surgery, radiation therapy, and oncology have reduced the incidence and improved treatment options.

However, the mortality rate is still high and often associated with the spread of malignant cancer cells to other sites, with the liver as the most common site of metastatic colonization.

The innovative delivery strategy of interferon alpha

The anti-tumor properties of interferon alpha are now recognized in the medical field. However, systemic delivery at relatively high doses has shown limited efficacy, mainly due to severe side effects throughout the body.

To improve the pharmacokinetic profile of interferon-alpha, making it more effective and tolerable, researchers at San Raffaele developed this new strategy. On the one hand, the drug is used at low doses; on the other hand, it is administered in the peri-operative phase, which is considered a critical time in the metastatic dissemination of cancer cells.

Adds Sitia, "In this way, interferon, released continuously, before and after surgery, is able to stimulate liver endothelial cells and orchestrate its multiple anti-tumor functions, while avoiding the toxic effects of high-dose administration."

Future applications

"Our results provide, at the preclinical level, encouraging evidence of the efficacy and safety of the strategy. It is now necessary to evaluate, with further studies, which patients with primary colorectal cancer might best benefit from this peri-operative therapy and prepare for clinical trials that could begin in a few years," Giovanni Sitia concludes.

Slow-release interferon alpha, already approved for clinical use, could thus be used as immunotherapy before and during surgery to remove primary colorectal tumors, especially in patients at increased risk of developing liver metastases.