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Immunotherapy is effective for many types of cancer, but colon cancer isn’t always one of them. Elena Popova/Getty Images
  • New research shows potential reasons as to why immunotherapy often doesn’t work for people with colon cancer.
  • Researchers say people with colon cancer often experience DNA mismatch repair deficiency, which in turn leads to a high tumor mutation burden.
  • They report that Immunotherapy tends to work better in clonal mutations, where all cancerous cells share the same mutation.
  • More research is needed, but the data could help doctors deliver more personalized cancer therapies to their patients.

Recent research has shed new light on some of the possible reasons immunotherapy is often ineffective for people with colon cancer.

In a paper published on September 14 in Nature Genetics, researchers analyzed the effects of immune therapy on mice with DNA mismatch repair deficiency (MMRd), a condition in which the body cannot correct DNA replication errors.

This process can cause tumors to mutate, creating a high tumor mutation burden (TMB). Both MMRd and TMB are frequently seen in people with colon cancer.

Because MMRd generates mutations, conventional wisdom says that it also generates potential new antigens and, hence, a positive immune response as the body is better equipped to recognize tumors.

However, researchers were surprised to find this wasn’t necessarily the case.

Dr. Peter Westcott, a study author and an assistant professor and cancer center member at Cold Spring Harbor Laboratory in New York, told Medical News Today:

“We expected that our models would show something similar to the clinic, where some mice might respond [to immunotherapy] while others wouldn’t. But we saw a universality across the board that these tumors are not immunogenic, which was a very surprising result.”

This negative result opens up intriguing questions and potential new avenues to treating people with colon cancer.

If the body is primed to respond to immunotherapy because it’s accustomed to tumor mutations, why does immunotherapy fail to work with so many people with a high tumor mutation burden?

Dr. Westcott hypothesized by comparing a tumor with few mutations to a tree, where everything grows from one central trunk, while a tumor with TMB is more like a bush or a shrub with divergent parts branching off in different directions.

“These tumors have their own sets of many mutations, but very few of these mutations are shared across all the tumor cells,” Dr. Westcott told MNT. “So if you just pick a couple of cells from one part of the tumor and a couple more from another part, you’ll find lots of mutations – but very few are actually shared.”

This means that while tumor mutations are widespread, they may not be able to trigger an immune response from the body because they’re so different from one another.

Dr. Westcott and his colleagues also found that mice with clonal mutations (shared by all cancer cells) were more responsive to immunotherapy than those with subclonal mutations (only shared by a subset of cancer cells).

This supports the theory that similar mutations respond to immunotherapy, while disparate mutations can have a negative impact.

Dr. Anton J. Bilchik, a surgical oncologist, surgery professor, and the chief of medicine at Saint John’s Cancer Institute in California, told MNT the new research is timely. Dr. Bilchik was not involved in the study.

“One of the issues [with immunotherapy] is that we know it works in a subset of patients, but it doesn’t work in everyone, and secondly, the response to immunotherapy is not always durable,” he said.

“What this paper does, is it sheds some light as to why that may be the case. It suggests that not every immune cell or T cell within a cancer is the same, so it provides some insight as to why immunotherapy may work in a subset of people and why the response may not be long.”

— Dr. Anton J. Bilchik, surgical oncologist

The new data could help doctors deliver more personalized treatment to people with colon cancer.

As things stand, Food and Drug Administration (FDA) guidelines state that a high tumor mutation burden can qualify people for immunotherapy. But the recent data suggests that this may not be the best metric.

“If you delve into it, you’ll find that it doesn’t actually inform treatment that much because there are other molecular indicators that are more informative, like MMRd and melanoma,” said Dr. Westcott.

“We now have a potential biomarker, which would be able to tell us whether you’re likely to respond to immunotherapy or not, which is really critical. Maybe there are other strategies we can take to increase your likelihood of responding, so this could be valuable for clinical testing. But that’s going to require future clinical studies to follow up on,”

— Dr. Peter Wescott, study author

Research like this could lead to a more nuanced understanding of how to treat patients with MMRd, TMB, and colon cancer.

As the third-most commonly diagnosed cancer in the United States, doctors frequently see colorectal cancers. Early warning signs include precancerous polyps in the large intestine. Risk factors include:

  • obesity
  • smoking
  • moderate to heavy alcohol intake
  • poor dietary habits (i.e., high consumption of processed meats)
  • other medical conditions (i.e., ulcerative colitis)
  • genetic factors

Hereditary conditions can also play a role.

Even if you have no symptoms and no risk factors, it’s recommended that anyone over the age of 45 get screened. Ongoing monitoring can include:

  • fecal testing
  • colonoscopy
  • sigmoidoscopy

Recent advances have made immunotherapy a more viable option for treating cancer, even if using it for colon cancer specifically remains a moving target.

“We never would have thought 20 years ago that up to 50% of patients with stage 4 melanoma, for example, would respond to immunotherapy,” said Dr. Bilchik.

“With colorectal cancer and other gastrointestinal cancers, the story is very different because it’s a much smaller percentage of patients that respond, and that’s why the selection of patients within the therapy has to be very specific. This is a very important study which hopefully will lead to a better understanding of how to use immunotherapy, and how to increase the number of patients that respond to immunotherapy.”

— Dr. Anton J. Bilchik, surgical oncologist