During tumor progression, cancer cells can colonize various organs, including the liver, giving rise to metastases. Liver metastases derived from gastrointestinal tumors are characterized by a modest response to current pharmacological therapies, including the most recent immunotherapy. Resistance of liver metastases to pharmacological therapies is associated with poor activation of immune cells present in the liver.

A group of researchers from the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) has developed a new gene therapy strategy capable of engineering some of the immune cells present in the liver (liver macrophages or Kupffer cells) in vivo in experimental models, with the aim of reactivating immune responses of this organ. The researchers managed to prevent systemic toxicity and to turn the tumor microenvironment from immunosuppressive to activating the anti-tumor response, thus achieving inhibition of metastases growth.

The study - published today in the prestigious journal Cancer Cell is coordinated by Professor Luigi Naldini, Director of SR-Tiget and Full Professor at the Vita-Salute San Raffaele University, and by Mario Leonardo Squadrito, Project Leader of the of the Targeted Cancer Gene Therapy Unit – lays the foundations for a future clinical development of a new gene therapy strategy for patients suffering from liver metastases.

First authors of the study are Thomas Kerzel and Giovanna Giacca, who carried out this work as part of their PhD studies. The work was mainly funded by AIRC5x1000 and FRRB.

Liver metastases

The presence of liver metastases derived from gastrointestinal tumors, such as colorectal carcinoma and pancreatic ductal adenocarcinoma, is a negative prognostic factor. Despite advances in pharmacological treatments, such as immunotherapy and tumor-targeted approaches, the most effective therapeutic option remains surgical resection, which is not applicable to all patients and often leads only to a partially successful outcome.

The high incidence of liver metastases is partly attributed to the immunosuppressive tumor microenvironment of this organ, which inhibits protective immune responses and, conversely, activates a series of pro-tumor mechanisms.

“For some years we have been focusing on the use of gene therapy techniques also in the oncology field, and this study is a new example of our commitment. Our goal is to respond to the unmet medical needs of all those patients suffering from inoperable liver metastases, for whom today no curative treatments are available ", explains Professor Luigi Naldini.

The use of gene therapy against liver metastases

San Raffaele researchers have developed a new gene therapy platform, based on lentiviral vectors, which allows the selective engineering of liver macrophages. Macrophages play an important role in regulating immune responses. While they help defend us from infections, when they are recruited to a tumor they can instead suppress other immune cells and promote neoplastic growth.

“With this new platform we can administer the vectors directly in vivo – with a single intravenous infusion – and they selectively reach the macrophages of the liver, in particular those recruited to the metastases” explains Mario Leonardo Squadrito. Genetically modified macrophages release immunostimulatory molecules, in particular type I interferon (IFNα). IFNα plays an important role in awakening our body's defense system by stimulating T lymphocytes, which recognize and kill tumor cells.

“With our approach we can reprogram the tumor microenvironment towards immune activation. However, we have noticed that some mechanisms of the liver (which, once again, tends to suppress immune responses) also create resistance to IFNα itself. We therefore combined the release of IFNα with an immunotherapy that is already used for other tumors and is based on the blockade of inhibitory lymphocyte receptors: this combination allowed us to further strengthen the immune response against metastases", specifies Squadrito. Thanks to a more permissive microenvironment, established following the engineering of macrophages, immunotherapy has demonstrated high therapeutic success in experimental models of liver metastases from colon and pancreatic cancer.

Future developments

Although this study is at present limited to experimental models, many of the results obtained by the San Raffaele researchers show clinical correlations that support their relevance.

“Overall, these findings lay the foundation for the clinical development of a new gene therapy strategy for patients with liver metastases. Further studies are now necessary to determine its safety and compatibility for use in humans,” concludes Naldini.