Promising New Combination Therapy Discovered For Some Types of Lung Tumors

Scientists have reported a discovery that a combination of immunotherapy and a gene mutation-blocking drug may help fight against certain lung cancers.

Lung Cancer

Lung Cancer

Lung cancer is a major cause of death worldwide. It accounts for most cancer-related deaths, with an estimated 1.8 million dying from it every year.

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Some patients get better after receiving immunotherapy, but this treatment does not help most. As a result, only around 25 percent of people with the disorder survive for more than five years after diagnosis. There is, therefore, an urgent need to find more effective therapy options.

The new study by researchers at the Francis Crick Institute not only shows the new combination therapy may help but could also aid in choosing subjects for clinical trials to confirm its efficacy.

The research appeared in the journal Science Advances.

Promising combination therapy

Specifically, scientists probed the effects of a combination of immune checkpoint blockade and KRAS-inhibitors in mice in this study.

A KRAS inhibitor blocks the KRAS gene, which belongs to the RAS gene family. Genes in this group are thought to play a role in many cases of cancers, including melanoma, pancreatic cancer, and bowel cancer.

“In recent years, there has been a lot of attention on whether combining immune checkpoint blockade, a type of immunotherapy, with a KRAS-inhibitor could be effective. This inhibitor works by blocking a mutated version of KRAS, a gene that helps control cell growth and death,” explained study author Julian Downward, an associate research director at the Francis Crick Institute. “As the mutation is present in about one third of lung cancer cases, it is a promising therapeutic target.”

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The research team found that the combination therapy effectively controlled cancer when tumors already had high amounts of active immune cells – that is, the so-called “immune hot” tumors. The treatment failed to impress in cases where a strong immune response was lacking.

A probe into the impact of KRAS gene mutation on tumors revealed that mutation reduces signals that aid in triggering the immune system. At the same time, mutated KRAS help to increase the amounts of hormone-like molecules that are favorable to tumors.

The environment became less conducive for tumors when scientists blocked the mutated gene in mice. A drop was seen in the number of cells that typically weaken the immune system. There was also a surge in cytotoxic T cells to help get rid of cancerous cells more effectively.

Designing future KRAS-inhibitor trials

The first KRAS-inhibitor got approval last year for use in some “non-small-cell lung cancer cases with the KRASG12C mutation.

Currently, there are different clinical trials probing how KRAS-inhibitors combined with immune checkpoint blockade can help patients. A big problem, however, is that majority of these trials involve only patients who did not respond to immune checkpoint blockade previously.

A lack of response to immunotherapy implies that the tumors of those patients were not “immune hot.” Findings from this study suggest that such patients are less likely to respond to the combination therapy.

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The scientists noted that there was still a lot to discover about KRAS inhibitors since they are still very new. More needs to be learned about when their efficacy is at the highest and what other treatments they can be safely combined with. This work will guide the right approach to adopt for future clinical trials, the researchers hoped.

Also, the team called for the inclusion of patients having “immune hot” tumors in clinical trials. This will ensure that the combination therapy is tested on those that are most likely to benefit.

The Crick researchers revealed plans to continue to probe the part played in cancer by the RAS family of genes. They will also explore how the immune system can be boosted to destroy cancer cells that are resistant to RAS inhibitors.

References

Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers

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