Cancers of the colon and rectum haven’t yet been as effectively treated with immunotherapy as have melanoma and lung cancer, but researchers are increasingly identifying patients who do appear to benefit from the immunity-boosting drugs – and devising strategies they hope will expand the reach of immunotherapy in colorectal cancers.
The main agents that have made immunotherapy an exciting and promising tool in cancer treatment are checkpoint blockers. These drugs, such as those that block CTLA-4, PD-1, and PD-L1, free the immune system to attack cancers that have managed to hide from immune defenses. In some patients with advanced melanoma and lung cancer, checkpoint blockers have enabled immune T cells to shrink or eliminate tumors, with long-lasting effects.
But when checkpoint blockers were first tested several years ago in patients with advanced colorectal cancers, the results were disappointing: They showed little activity against the tumors in most patients. But the studies did reveal a small category of colorectal cancer patients whose tumors did respond to the immunotherapy. These were patients whose cancer cells had a defect in their ability to repair a particular kind of damage to their DNA blueprint. Such cancers are said to show high “microsatellite instability,” or MSI, and are deficient in repairing mismatched chemical letters of the genetic code.
In one study, patients with high MSI scores treated with the PD-1 inhibitor pembrolizumab had a 40 percent response rate – meaning their tumors shrank – compared to no responses in patients whose cancers did not have MSI.
It is estimated that about 15 percent of patients with colorectal cancer are MSI-high, and therefore can be treated with checkpoint blockers such as pembrolizumab.
It’s thought that immunotherapy works better against cancers with defective DNA repair mechanisms because those tumors carry many more DNA mutations, and those mutations cause the cells to produce abnormal proteins that stimulate the immune defenses to attack the defective cells. But what can be done to improve immunotherapy results in the 85 percent of patients whose colorectal cancers are not MSI-high?
Rahma has proposed one strategy – combining pembrolizumab with radiation therapy for colorectal cancers. It has been shown that cells killed by radiation release molecules that are recognized by T cells, which then swarm to the tumor environment. This notion will be tested in a large national trial in rectal cancer led by Dana-Farber.
Another strategy is to combine immunotherapy checkpoint inhibitors with targeted therapies – drugs that inhibit cancer growth by binding to a specific molecular defect in the cancer cell. Clinical trials of this approach are ongoing.
Studies are also beginning involving different antibodies to block more than one immune checkpoint that the cancer cells are using to escape immune attack, or to block a checkpoint while simultaneously stimulating the immune system with another molecular agent.
“Right now the field is wide open to test a lot of novel hypotheses aiming to change the landscape of colorectal cancer treatment and improve its outcome,” Rahma says.