Mouse study shows combination treatment improves response to lung cancer immunotherapy

Researchers at the Francis Crick Institute, in collaboration with Revolution Medicines, tested a combination of treatments on mice with lung cancer and showed that these allowed immunotherapies to target non-responsive tumours.

Their results show that targeting tumors in different ways simultaneously could increase the response to treatments.

In research published in Nature CommunicationsScientists tested a combination of tool compounds on mice with lung cancer. These compounds were used to represent:

• Targeted drugs that block a cancer-causing protein called KRAS^G12C:These drugs have been approved for the treatment of lung cancer, but they often do not benefit patients in the long term because tumors develop resistance to these drugs over time.
• Immunotherapy drugs: These are designed to stimulate the immune system to fight the tumor, but only 20% of people with lung cancer respond to them because tumors often block the entry of immune cells.

The researchers combined a newly identified KRAS^G12C inhibitor, with a compound that blocks a protein called SHP2, which inhibits cancer cells and can also activate tumor immunity.

These two inhibitors were combined with an immune checkpoint inhibitor, which blocks proteins that help cancer cells hide from the immune system.

In mice with functioning immune systems, the combination of three antibodies shrank tumors and, in some mice, completely eradicated them. These mice were also more resistant to lung cancer recurrence after treatment.

The team believes these targeted compounds provide a window of opportunity where the immune checkpoint inhibitor can kick in and allow the body’s natural defenses to attack the tumor.

Even in mice with so-called “immune cold” tumors that do not normally respond to immunotherapy, the combination allowed the tumors to become sensitized to the immune checkpoint inhibitors.

Given the success of the mouse studies, an evaluation of this combination could be conducted in people with lung cancer to determine if it has a similar effect. Research will also be needed to understand and counteract potential side effects associated with the combination of treatments.

Julian Downward, Senior Group Leader in the Crick’s Oncogene Biology Laboratory and co-senior author with Miriam Molina-Arcas, said: “Blocking genes like KRAS in lung cancer has led to exciting new developments, but we still see problems with resistance.

“We were able to observe partial or complete eradication of tumors in mice by combining KRAS and SHP2 inhibitors with immunotherapy. We also showed that this combination therapy allows “cold immune” tumors to respond to the body’s natural defenses.”

Panos Anastasiou, PhD student in the Crick’s Oncogenic Biology Laboratory and first author, said: “Our work highlights the importance of targeting tumours from all angles, particularly those that do not respond readily to treatment. It will be essential to see whether the combination of inhibitors works in the same way in humans.”

Panos has worked with the Crick’s experimental histopathology, bioinformatics and biostatistics, genomics, scientific computing, flow cytometry, cellular services and biological resources teams.