“They work by blocking signals in a tumor that stop the immune system from working,” says Scott Kopetz, M.D., Ph.D. By preventing these signals, checkpoint inhibitors allow immune cells called T cells to target cancer.
Pembrolizumab and nivolumab are the two immune checkpoint inhibitors that have been most effective in treating colorectal cancer. They’re approved by the Food and Drug Administration for patients with a subtype of metastatic colorectal cancer called microsatellite instability-high disease.
What is microsatellite instability-high colorectal cancer?
Patients with microsatellite instability-high (MSI) colorectal cancer have a lot of genetic mutations inside a tumor that fuel its growth. Kopetz says patients may also hear the term “deficient mismatch repair” (dMMR) to describe this subtype.
Microsatellite instability status is determined through a molecular profile, which is a series of tests performed on tissue that’s removed during biopsy to learn a tumor’s genetic makeup. “Right now, this is primarily done to help match a patient to a clinical trial,” Kopetz says.
A clearer distinction between cancer and normal cells
To the immune system, foreign pathogens look very different from normal cells. But the difference with cancer cells isn’t as clear – except in microsatellite instability -high disease.
“Patients with MSI-high colorectal cancer are more likely to have their immune systems detect the tumors are different from normal tissue,” Kopetz says.
This helps lay the groundwork for immunotherapy to be effective. “The good news is the immune cells often recognize the cancer cells as different,” Kopetz says. “The barrier is the checkpoints – or the signals – that the tumor cells put on their surface to prevent the immune cells from attacking.”
This is where immune checkpoint inhibitors come in. They block the signal from the tumor cells that prevents the T cells from doing their work.
Unfortunately, only 3% of patients with metastatic colorectal cancer have MSI-high disease.
“It’s very low,” Kopetz says. “But for the first time, there’s a subset of patients where we can say, ‘Despite having metastatic disease, we can cure you with immunotherapy.’” He says that hasn’t been possible with chemotherapy and targeted therapies.
Discovering other colorectal cancer subtypes
MD Anderson researchers are working to discover other, less common subtypes of colorectal cancer that may also have high mutation loads. One possible opportunity are the mutations within the POLE gene.
“We’ve shown that tumors with POLE mutations can be another subgroup that can be very responsive to immunotherapy and can have complete responses as well,” Kopetz says. Efforts are underway to better understand which patients fall into the subgroup and can benefit from these drugs.
Research seeks to break into the tumor microenvironment
Of the remaining 97% of patients with metastatic colorectal cancer who don’t fall into the subset of MSI-high disease, it’s thought they can be divided into two groups, Kopetz says. He and colleagues have developed a tool called the consensus molecular subtype classification system to aid in subtyping patients.
The first group is patients with CMS4 tumors. Their T cells are activated and wanting to attack, but they can’t enter what’s called the tumor’s microenvironment. “It’s like the tumor sets up a chain link fence that keeps them out,” Kopetz says. When examined under a microscope, the T cells cluster along the edges of a tumor, trying to get in.
Research is aimed at breaking down the chain link fence to allow the T cells to enter the tumor microenvironment. Once inside, it’s hopeful that the T cells can be effective in killing the tumor with the help of immunotherapy.
“It’s not about activating the immune system; that's done thanks to immunotherapy,” Kopetz says. “It's about targeting the tumor microenvironment to get the T cells inside first.”
Overcoming the immune desert
In patients with CMS2 or CMS3 colorectal cancer, though, the T cells show little to no activity in response to the tumor. “We refer to it as the immune desert,” Kopetz says. When viewed under the microscope, the immune system shows little evidence of reacting.
“The strategy is less about the tumor microenvironment – which may still be a problem – and more focused on getting the immune system to even recognize that there's something going on,” he says. Through MD Anderson’s Colorectal Cancer Moon Shot™, Kopetz oversees research exploring new ways to address this challenge.
One approach is personalized vaccines. They work by instructing the patient’s cells to produce proteins based on the mutations driving the cancer’s growth. The immune system then searches for other cells with the mutated proteins to clear them out.
Another opportunity is with cellular therapies like CAR T cell therapy, T cell therapy and CAR NK cell therapy, which are being explored through clinical trials. “With T cell therapies, we’re trying to take the few, rare T cells that are in the tumor, expand their numbers in a lab and give them back to the patient,” Kopetz says. “Or, we’re trying to manufacture T cells that we design in a lab to be better equipped to attack the cancer.”
Oncolytic viruses are another research focus. A virus is injected into the tumor and is then replicated within the cancer cells. When the immune system targets the virus, the hope is it will also target the mutations within the cancer cells.
“It’s a very different understanding of colorectal cancer,” Kopetz says. “But we hope that by learning more about the differences between these subtypes, we can direct these new treatment approaches in the most effective way to benefit more patients.”