Immunotherapy and colorectal cancer: Where we are and what’s ahead

The immune system defends the body from viruses and bacteria. But it’s not as successful in killing cancer on its own. Immune checkpoint inhibitors – a type of immunotherapy – harness the immune system to treat many types of cancers, including colorectal cancer.

They work by blocking signals in a tumor that stop the immune system from working. By preventing these signals, checkpoint inhibitors allow immune cells – called T cells – to target cancer.

Here, I’ll share more about how immunotherapy is used to treat colorectal cancer and the research we’re doing at UT MD Anderson.

Which immune checkpoint inhibitors treat colorectal cancer?

There are four immune checkpoint inhibitors that have been most effective in treating colorectal cancer.

• pembrolizumab
• nivolumab
• ipilimumab
• dostarlimab

They’re approved by the Food and Drug Administration (FDA) for patients with a subtype of metastatic colorectal cancer called microsatellite instability-high (MSI-H) disease.

What is microsatellite instability-high colorectal cancer?

Patients with microsatellite instability-high colorectal cancer have a lot of genetic mutations inside a tumor that fuel its growth. Patients may also hear the term “deficient mismatch repair” (dMMR) or “mismatch repair (MMR) deficient” to describe this subtype.   

These genetic mutations are sometimes linked to a hereditary syndrome called Lynch syndrome, but sometimes they occur sporadically. This means they aren’t passed down through a family member.

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. Molecular profiling is considered universal testing, so all colorectal cancer patients should undergo it. It can help guide immunotherapy treatment.

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-H disease.

Patients with MSI-H colorectal cancer are more likely to have their immune systems detect that tumors are different from normal tissue. This helps lay the groundwork for immunotherapy to be effective.

The good news is the immune cells often recognize the cancer cells as different. 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. 

Only 3% of patients with metastatic colorectal cancer have MSI-H disease.

But this is a subset of patients where we can say, “Despite having metastatic disease, we can cure you with immunotherapy.” That hasn’t been possible with chemotherapy and targeted therapies.

Discovering other colorectal cancer subtypes

UT MD Anderson researchers recently discovered a less common subtype of metastatic colorectal cancer that responds well to immunotherapy.

They led a study that found that tumors with a specific subtype of mutations in the POLE gene, called loss-of-proofreading (LOP) mutations, are very responsive to immune checkpoint inhibitors. These findings are important because not all POLE mutations behave in the same way. We now know that patients we identify with the LOP subtype may benefit from immune checkpoint therapy.

Overcoming barriers to treat metastatic colorectal cancer

We believe the remaining 97% of patients with metastatic colorectal cancer that isn’t MSI-H can be divided into two groups. My colleagues and I have developed a tool called the Consensus Molecular Subtype (CMS) classification system to help subtype colorectal cancer.

CMS4 tumors

One group is patients with CMS4 tumors. Their T cells are activated and want to attack cancer, but they can’t enter the tumor’s microenvironment. It’s like the tumor sets up a chain link fence that keeps them out. When examined under a microscope, the T cells cluster along the edges of a tumor, trying to get in. 

This is the case with colorectal cancer tumors that have spread to the liver. Instead of the T cells being spread throughout the tumor, they are mostly located near the edge, making them less effective. In analyzing these types of tumors, we’ve discovered that the tumor microenvironment in the liver looks different than other parts of the body. Namely, it’s full of immune cells that cause immunosuppression and do not help control cancer.

Our research is aimed at breaking down the chain link fence to allow the T cells to enter the tumor microenvironment. Once inside, we hope 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. It's about targeting the tumor microenvironment to get the T cells inside first.

CMS2 and CMS3 tumors

In patients with CMS2 or CMS3 colorectal cancer, the T cells show little to no activity in response to the tumor. We refer to it as the ‘immune desert.’ 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 about getting the immune system to even recognize that there's something going on.

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 take the few, rare T cells that are in the tumor, expand their numbers in a lab and give them back to the patient. Or, we manufacture T cells that we design in a lab to be better equipped to attack the cancer.

Research to find and treat metastatic colorectal cancer earlier

A big part of the research we’re doing now is developing new strategies to treat micrometastatic colorectal cancer. This is cancer that has spread from the primary tumor in tiny amounts – too small to be seen on traditional scans or blood tests. It is sometimes referred to as minimal residual disease (MRD). Patients with MRD are more likely to have a cancer relapse.

We’re researching how we can detect MRD through circulating tumor DNA (ctDNA) testing. We know as tumors get bigger and the number of cancer cells increases, they start building up defenses against the immune system. This is when immunotherapy becomes less effective.

Based on earlier research, we know that really small micrometastatic deposits can be sensitive to immunotherapy. So, we want to identify the cancer earlier – even before scans pick them up – and find immunotherapies to best treat these patients. There are a few different immunotherapy combinations being explored in clinical trials right now.     

We’re excited about the progress that’s been made in immunotherapy to treat colorectal cancer, and we hope to develop new ways to benefit even more patients.

Scott Kopetz, M.D., Ph.D., is a gastrointestinal medical oncologist and associate vice president for translational research at UT MD Anderson.

Request an appointment at UT MD Anderson online or call 1-877-632-6789.