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Immunotherapy could help treat advanced forms of colorectal cancer. Amornrat Phuchom/Getty Images
  • Colorectal, or bowel, cancer is the third most common cancer worldwide, and the second leading cause of cancer deaths.
  • Treatments include surgery, radiotherapy, chemotherapy, or immunotherapy, but the efficacy of treatment depends on the type of bowel cancer the person has.
  • A phase 1 trial has found that two monoclonal antibodies could be effective against a common form of colorectal cancer that has, historically, not responded to immunotherapy.
  • These findings could be a first step towards more effective treatment for people with this form of colorectal cancer.

According to the World Health Organization, around 10% of cancers worldwide are colorectal (bowel) cancer. In the United States, the American Cancer Society estimates that more than 150,000 people will be diagnosed with cancer of the colon or rectum in 2024.

The risk of colorectal cancer increases with age, and most cases are diagnosed in people over the age of 50. The cause is not clear, but is thought to be a combination of genetic and environmental risk factors, including:

  • Male sex
  • A diet low in fiber, and high in animal protein, particularly red and processed meats, and saturated fats
  • Overweight or obesity
  • Smoking and alcohol consumption
  • Low levels of physical activity
  • Inflammatory bowel disease.

Treatment is more effective if the cancer is detected early, and may include surgery to remove the tumor, radiation therapy or chemotherapy to destroy cancer cells and shrink the tumor, and immunotherapy.

However, immunotherapy is effective against only some types of colorectal cancer. Now, a phase 1 trial has found that a combination of two monoclonal antibodies — botensilimab and balstilimab — was effective in 61% of people with advanced MSS colorectal cancer.

The study is published in Nature Medicine.

Justin Stebbing, professor of biomedical sciences at Anglia Ruskin University (ARU), U.K., and communicating author of the study, told Medical News Today:

“It’s the first time we’ve consistently seen durable responses in the heavily pre-treated patients with colon cancer, so I think it’s hugely exciting, especially as this affects so many people.”

All the patients in the study had microsatellite stable metastatic colorectal cancer (MSS mCRC). This common form is sometimes referred to as ‘immune cold’ as, unlike other forms of colorectal cancer, it has previously proved resistant to immunotherapy.

“It opens the door for immunotherapy to work in ‘cold tumors’, either those cancers that typically don’t respond to immunotherapy, or even those who have previously responded and done well, but then it’s stopped working. So it potentially has very broad applicability across tumor types,” Prof. Stebbing told Medical News Today.

In this study, the researchers recruited 148 patients with solid bowel tumors that had metastasized (spread to other parts of the body). All had undergone several previous treatments for their cancer.

They treated them initially with escalating doses of botensilimab, then with a combination of botensilimab and balstilimab.

Of the total cohort, 101 patients completed the six-months follow-up required for the evaluation of the treatments.

“In cancers that are shown to have broken repair mechanisms (MSI high or dMMR), it is known that immunotherapy can help. These immunotherapies allow the body’s natural immune system to better recognize cancer cells and attack them. […] However, immunotherapy has generally been ineffective in cancers than have intact repair mechanisms [such as MSS mCRC].”

Dr. Daniel Landau, oncologist, hematologist and contributor for The Mesothelioma Center at Asbestos.com, who was not involved in the study.

The researchers reported ‘encouraging efficacy’ across different tumor types in the trial. They looked at several endpoints, including complete and partial response to treatment.

Following combined therapy, 62 of the 101 patients showed some response, as Stebbing explained:

“Of the patients in the phase 1 trial, 101 took part in a six-month follow-up and of these, 61% of them saw their tumor shrink or remain stable after receiving a combination of botensilimab and balstilimab.”

Landau welcomed the findings:

“There has been a lot of interest in developing immunotherapies that can work for these cancers too. Botensilimab plus balstilimab may be the answer we’ve been searching for.”

Some patients had metastases on their livers, so the researchers investigated whether this affected their response to the treatment.

They found that in people with active liver metastases, response and survival times were significantly lower than in those without liver metastases.

Stebbing explained why:

“We know that disease in the liver can have specific effects on the immune system, so as these drugs work by harnessing the activity of specific T cells to fight cancer, it’s possible that liver disease can affect the treatment in that way.”

“It appears that folks with liver disease didn’t respond as well. This could be for several reasons. Unfortunately, when the disease makes the leap into the liver, it is often more aggressive and more difficult to treat,” Landau added.

“Traditional chemotherapies may be more important for this population. As more studies are done, we will better understand how the combination works and when it’s best used,” he told MNT.

Many cancer treatments have severe side effects, but immunotherapy is generally tolerated better than some other treatments, such as chemotherapy.

In this study, 89% of participants reported treatment-related adverse effects (TRAE), including fatigue, diarrhea and pyrexia (raised body temperature). In total, 52 people experienced serious TRAEs, but there were no treatment-related deaths during the study.

Landau emphasized that this was to be expected:

“The primary purpose of a phase 1 study is to find the safety of medications or combinations. […] At least in early results, most patients were able to tolerate the combination of botensilimab and balstilimab. The side effects seem to be fairly typical for immunotherapies, and most people tolerate immunotherapies better than chemotherapies.”

“[This trial] focuses on the efficacy and safety of botensilimab (BOT), an Fc-enhanced anti-CTLA-4 antibody, in combination with balstilimab (BAL), an anti-PD-1 antibody. Together, these therapies are designed to activate the immune system against a cancer type historically resistant to immunotherapy.”

— Prof. Justin Stebbing

Landau explained that these early findings will need to be verified in further trials:

“In a small study designed to look at the safety of this combination, it appears there was a response to the therapies in this population. However, it is important to understand that this was a very small study, so larger studies that compare this finding need to be conducted,” he said.

Stebbing voiced optimism that the trial might lead to a better prognosis for people with this type of cancer:

“While overall death rates from colorectal cancer have declined, survival rates for advanced disease remain poor, with an increasing burden on younger populations. For the 95% of patients diagnosed with MSS mCRC, there are no approved immunotherapies, making long-term survival exceedingly rare. I hope this changes that.”