UCSF team discovers breakthrough immunotherapy to treat colon cancer liver metastases

Advanced colorectal cancer is the leading cause of cancer death among young American men and the second most common cause worldwide. Most of these patients develop liver metastases as the cancer progresses. Despite advances in surgical treatments to eliminate the cancer, many of these patients will experience a recurrence of the cancer in the liver.

Now, researchers at the University of California, San Francisco (UCSF) have discovered that a novel combination of immunotherapies can reprogram the immune environment of colorectal cancers that have spread to the liver. In preclinical models, this therapy often completely eradicated tumors, offering a potential new treatment path for patients with advanced colorectal cancer.

Their study appears October 8 in .

Given that most of the liver metastasis are resistant to current immunotherapies, our goal was to develop new therapies that strengthen the immune system to recognize cancer and fight it permanently. We have demonstrated that a novel combination of immunotherapies can alter the immune microenvironment of colon cancer liver metastases, often eliminating tumor formation in a preclinical model.”

Ajay V. Maker, MD, FACS, FSSO, senior author of the study, Maurice Galante, distinguished professor of surgery, surgeon-in-chief of the UCSF Helen Diller Family Comprehensive Cancer Center and chief of surgical oncology at UCSF

Previous studies have shown an unprecedented response of immune checkpoint blockade in other cancers.However, they found that immune checkpoint blockade (ICB) did not result in a clinically significant response in microsatellite-stable (MSS) colon cancer, which accounts for more than 95% of colon cancers. These tumors rarely respond to checkpoint blockade alone or in combination, and studies have shown that the response rate to ICB in many tumors is lowest when liver metastases occur.

To overcome this immunotherapy resistance, researchers have used the strategic targeting of specific signals in and around liver metastases to activate the immune system and synergize with immunotherapy to control MSS tumors. Their team previously showed that overexpression of the immunostimulatory cytokine TNFSF14/LIGHT (a signaling protein) is associated with increased numbers of tumor-infiltrating lymphocytes (T cells) and improved survival in advanced colorectal cancer.

In the current study, they developed a mouse model of colorectal liver metastasis to demonstrate that LIGHT monotherapy activates T cells and recruits immunosuppressive elements that can work together with other immunotherapies to control and often kill these tumors.

Because colorectal liver metastases express high levels of the CTLA-4 protein receptor, the research team combined LIGHT overexpression with anti-CTLA-4, which led to complete tumor control. Combining LIGHT with anti-CTLA-4 controlled colorectal cancer liver metastasis by altering the tumor microenvironment.

“In this study, we demonstrate how our unique strategy can train and reengineer immune responses to both recognize unique tumors and resist the suppression or premature depletion of cancer-fighting cells in a well-established preclinical model,” Maker said. “We are very excited about this work and inspired to continue translating the results for use in patients.”

Maker adds that they are developing strategies to strategically deliver immunotherapy directly to the liver and metastatic tumors. Because anti-CTLA-4 is administered to patients systemically, he believes this combination therapy has both applicability and high feasibility.

“This study represents a huge step forward in understanding the basis of these liver metastases and shows that strategically targeting specific signals can activate our immune system in a way that can kill these tumors,” Maker said.