Immunotherapy combo targets mutation found in up to 25% of all cancers
Scientists at the University of California San Francisco (UCSF) have found a way to fight one of the most common cancer-causing mutations. The new drug puts up an “eat me” marker that can help the immune system or other drugs find and kill the cancer.
Mutations in a gene called KRAS are implicated in as many as 25% of all tumors in humans, putting it high on the hit list of interest for scientists. The problem is, the KRAS protein has traditionally been hard to treat for a few reasons – for one, its surface is too “smooth” for drug molecules to latch onto. Thankfully, one promising drug called sotorasib, which counters this, is currently undergoing phase 2 clinical trials.
For the new study, the UCSF researchers investigated a way to target other inconvenient features of the KRAS protein – namely, that it’s so similar to the healthy version, and it operates inside cells rather than on the surface, making it hard for the immune system to recognize mutations.
The team found that a drug called ARS1620 can help with both of those issues. The molecule binds to mutated KRAS proteins well and not only blocks its influence on tumor growth, but also pulls the protein out to the cell surface. Once there, the protein and the drug, bound together, send out a signal that alerts the immune system to attack.
“The immune system already has the potential to recognize mutated KRAS, but it usually can’t find it very well,” said Kevan Shokat, co-lead author of the study. “When we put this marker on the protein, it becomes much easier for the immune system.”
Next, the team screened billions of human antibodies to identify those that best recognized this “eat me” signal. Studies on isolated proteins as well as human cells singled out one that was particularly effective at binding to both AR1620 alone and when it formed a complex with the mutated KRAS.
From this, the researchers developed an immunotherapy based on this antibody. In tests in alveolar cell carcinoma cells in the lab, the new immunotherapy paired with AR1620 was able to inhibit the cancer growth by 82%, up from 44% for the drug without immunotherapy. Intriguingly, this worked even when the tumors had previously developed resistance to AR1620 alone.
While it’s still early days for the study, the team says that it’s a promising proof-of-principle for fighting cancer using this combination of targeting drug and immunotherapy. Along with developing it towards eventual human tests, the researchers plan to investigate how the strategy might work against other tricky cancers.
The research was published in the journal Cancer Cell.