Immunotherapy is a promising cancer treatment, but getting it to work against solid tumors is proving difficult. A new study has not only identified a drug that’s effective against solid tumors, but may have uncovered a reason that immunotherapy often fails.
The human immune system is a powerful weapon, but cancer does a good job of hiding from it and creating an environment around itself that keeps immune cells out. Immunotherapy is an emerging treatment that allows scientists to supercharge the immune system against cancer, and while it’s had some success against things like melanoma and leukemia, the technique hasn’t translated well to solid tumors.
But new research into a drug that helps treat prostate cancer might have uncovered a mechanism for immunotherapy’s patchy record, and point to a way to fix it. Scientists at Washington University in St. Louis started out by testing a drug compound called (R)-9b, which in previous studies had proven promising against cancer. Since the drug is known to block a gene called ACK1, the team engineered mice to completely lack this gene and investigated how well they responded to cancer.
“In most of these mice, when we introduced cancer cells as we typically do, there was no trace of a tumor,” said Nupam Mahajan, senior author of the study. “In the few that did develop tumors, the tumors were small compared to those of wild-type mice. This was the first clue that something important was happening in mice missing this gene. We found that they were able to mount a robust immune response against the cancer cells.”
Next, the team tested (R)-9b in mice with the ACK1 gene. And sure enough, when the animals were implanted with human prostate cancer cells, they saw similar results to those lacking the gene entirely. The team saw increased levels of cancer-targeting T cells, and signaling molecules that helps them penetrate the tumors to kill them more efficiently. The third prong of the attack was to cut off prostate cancer’s fuel supply – testosterone.
The team went on to test whether this drug would work even better when paired with immunotherapy drugs known as immune checkpoint inhibitors. These work by essentially releasing the natural brakes on the immune system. Intriguingly, the researchers found that there was no improvement – in fact, the immunotherapy drug seemed to actively work against (R)-9b. This hints at a reason immunotherapy might fail in many solid tumors, and a potential way to get around it.
“Surprisingly, we found that the immune checkpoint inhibitor is activating ACK1, the very pathway we are shutting down with this drug compound,” said Mahajan. “It’s possible immune checkpoint inhibitors don’t work well in these tumors because they are turning on ACK1, which suppresses the immune response. Similar to prostate cancer, the ACK1 pathway activation also could be employed by other cancers that do not respond to checkpoint inhibitors. However, these cancers could respond to (R)-9b, so we would like to investigate this drug in other solid tumors as well.”
The research was published in the journal Nature Communications.
