Researchers have conducted tests using a mix of treatments on mice with lung cancer, demonstrating that this approach enables immunotherapies to effectively target tumors that typically do not respond.
A team from the Francis Crick Institute, in partnership with Revolution Medicines, has explored various treatment combinations in mice suffering from lung cancer. Their results indicate that tackling tumors using multiple strategies at the same time could enhance treatment effectiveness.
Their study, published today in Nature Communications, involved experimenting with a set of compounds on mice afflicted by lung cancer. These compounds were designed to simulate:
- Targeted medications that inhibit a cancer-promoting protein known as KRAS G12C. Although these drugs have been approved for lung cancer, they often provide limited long-term benefits due to tumors developing resistance over time.
- Immunotherapy agents aimed at boosting the immune system’s ability to combat tumors. However, only about 20% of lung cancer patients show a response, as tumors frequently obstruct immune cells from accessing the site.
The scientists combined a new KRAS G12C inhibitor with a SHP2-blocking agent, which not only inhibits cancer cells but also enhances tumor immunity.
This combination was further paired with an immune checkpoint inhibitor, which prevents cancer cells from evading detection by the immune system.
In mice with functioning immune systems, this triple therapy led to tumor reduction, and in some cases, complete elimination. Moreover, these mice exhibited increased resistance against the recurrence of lung cancer post-treatment.
The researchers speculate that these targeted agents create a timely opportunity for the immune checkpoint inhibitor to activate, allowing the body’s defenses to engage the tumor.
Remarkably, even in mice with “immune cold” tumors, which typically resist immunotherapy, the combination allowed tumors to become responsive to the immune checkpoint agents.
Following promising results in mice, there is a potential for further evaluation of this combined treatment in human lung cancer patients to assess if similar results can be achieved. Further research is also necessary to uncover any potential side effects that may arise from this combination of therapies.
Julian Downward, Principal Group Leader at the Oncogene Biology Laboratory at the Crick, and co-senior author with Miriam Molina-Arcas, remarked: “The efforts to target genes like KRAS in lung cancer have led to promising developments, but resistance remains a challenge. We have been able to report cases of partial or complete tumor eradication in mice through the use of KRAS and SHP2 inhibitors alongside immunotherapy. Our findings also indicate that this combination therapy can provoke a response in ‘immune cold’ tumors, stimulating the body’s natural defenses.”
Panos Anastasiou, a PhD student at the Oncogene Biology Laboratory and the lead author, added: “Our research highlights the necessity of addressing tumors from all possible angles, particularly those that are less responsive to existing treatments. It will be crucial to determine if the synergy of these inhibitors functions similarly in humans.”
Panos coordinated with multiple teams at the Crick, including Experimental Histopathology, Bioinformatics and Biostatistics, Genomics, Scientific Computing, Flow Cytometry, Cell Services, and Biological Resources. The study was supported by a collaborative research agreement with Revolution Medicines, along with additional backing from the European Union and the Wellcome Trust.
