Immunotherapy of hepatic metastases of colorectal cancer

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

Following administration with this novel modality, scientists observed that the drug was able to stimulate liver endothelial cells to build a vascular barrier. Thus, limiting the entry of cancer cells into the organ in question, thereby preventing metastasis formation.

"This result is possible due to 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," explains Giovanni Sitia.

Colorectal cancer is one of the highest incidence neoplasms in the world, and in Italy alone it ranks second in the male and female population for 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 being the most common site of metastatic colonization.

The anti-tumor properties of interferon-alpha are now recognized in the medical field. However, systemic administration 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 the Ospedale San Raffaele have devised 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.

"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," adds Dr. Sitia.

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

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