Immunotherapy Before Surgery May lead to Better Outcomes

  • A pair of immunotherapy drugs have shown impressive results in treating a subset of colorectal cancer known as mismatch repair-deficient (dMMR) colorectal cancer.
  • DMMR colorectal cancer is characterized by genetic mutations which make it easier for the immune system to identify.
  • The drugs resulted in a “major pathological response,” reducing tumor size to less than 10% in the vast majority of patients.

Colorectal cancer is notoriously resistant to immunotherapy options. But, for a subset of patients, a novel treatment shows promise,

Mismatch repair-deficient (dMMR) colorectal cancer is present in between 10-15% of all colorectal cancer patients and is characterized by a high number of mutations in genes responsible for repairing mistakes that can occur during DNA replication. While it can show up in other forms of cancer, including breast and prostate, it is most commonly found in colorectal cancer.

Treatment options for DMMR colorectal cancer can be tricky. On one hand, it tends to be more resistant to chemotherapy, but researchers have now been making inroads with immunotherapy.

Surgery is the primary treatment for colorectal cancer, but in research published this week in the New England Journal of Medicine scientists found that a pair of immunotherapy drugs administered before surgery significantly diminished tumor size without serious safety concerns.

Researchers set out to study the safety profile of the drugs by observing whether patients who took them would still be able to undergo surgery within an allotted time frame or if they would have to delay their surgery. About 98% of patients underwent timely surgery, meaning they had less than a two-week delay when taking the combination of drugs.

Researchers observed immune-related side effects in 73 patients, with severe (grade 3 or 4) events occurring in 5 patients. None of the patients discontinued treatment due to these adverse events.

The effects of the drugs on the tumors themselves were also surprising. The study found 95% of patients experienced a major pathological response, shrinking the tumor to less than 10% of its size. Meanwhile, Two-thirds of patients had a complete pathological response, meaning there was no residual evidence of the tumor after treatment.

More than two years after surgery, no patients experienced a recurrence of the cancer. The patients are being followed for longer to evaluate the durability of their response.

“I don’t think anybody expected these results or the extent of these results,” Kristen Ciombor, MD, an Associate Professor of Medicine at Vanderbilt University Medical Center who wasn’t affiliated with the study told Healthline.

“Two-thirds of patients didn’t have any tumor left, which is really incredible. It’s something that we don’t see at that rate and extent with pretty much any other therapy,” she said.

The study, conducted by researchers in the Netherlands, involved 115 patients with non-metastatic, locally advanced, previously untreated dMMR colon cancer. That’s a technical way of saying colorectal cancer which has developed beyond the earliest stages (patients in the study had either stage II or II cancer) but has still not spread (metastasized) to other organs in the body.

Doctors administered the patients two different immunotherapy drugs prior to surgery. The drugs, nivolumab and ipilimumab, belong to the same class of immunotherapy treatment, known as immune checkpoint inhibitors, but utilize unique biological mechanisms from one another.

“The greatest advance we’ve had in decades of cancer research has been in the field of immunotherapy. Developing immune treatments to help the immune system attack cancer is something that we’ve dreamed about since the 1950s,” George Fisher, MD, PhD, a Professor of Medical Oncology at Stanford Medicine, told Healthline.

The results of this latest trial demonstrate how far the field has come.

The concept of immunotherapy is simple to describe, but extremely complex to implement. When the body mounts an immune response it must identify friendly cells and foreign invaders. In order to do this, T cells, which are your body’s defenders in the immune response, perform a sort of “handshake,” known as an immune checkpoint, with healthy cells that marks them as safe. Without this, the T cells will attack.

Some forms of cancer can abuse this mechanism to hide from the immune system. Those cancers can then continue to grow without fear of an immune response.

Immune checkpoint inhibitors work by preventing cancer cells from faking this “handshake” and allowing the immune system to identify and kill them.

An additional complication is that colorectal cancer in particular tends to remain well hidden from immune system detection. But dMMR versions are different; the genetic mutations characteristic of dMMR make it easier for the immune system to pick out, and also more susceptible to immunotherapies.

“If you have more mutations, then you make more abnormal proteins. And if the immune system is capable of recognizing abnormal proteins, then those cells that have the most mutations are the ones most likely to have proteins that might be recognized as foreign,” said Fisher.

“The genetic mutations in these tumors makes it what we call ‘immunologically hot.’ So the immunotherapy can work better against the tumor itself,” said Ciombor.

Experts interviewed by Healthline said that there is still much more work to do before we can know if the immunotherapy treatments in the study will be safe and effective among a larger group of patients, but the results are exciting nonetheless.

“There’s no doubt that this study is very impressive and the fact that we can see such tremendous changes in such a short interval of time with treatment with both drugs really suggests that there is likely to be a subset of patients who will not need to go to surgery,” said Fisher.

Should trials continue to show safety and efficacy, certain groups of patients could have new options available to them. For example, older patients or those with certain comorbidities that make them an unsuitable candidate for surgery might be able to opt for immunotherapy.

Patients with low-grade cancer could also potentially elect not to have surgery, although the long-term outcomes of immunotherapy without surgery have not yet been established.

As with any treatment, there will be a question of risk versus benefit. An immunotherapy treatment prior to surgery might preclude the necessity for chemotherapy but at the risk of a severe complication called immunotherapy toxicity.

“It at least raises the possibility that there may be other options to treat this type of cancer,” said Ciombor.

“If you can avoid chemotherapy, that would be a win. Ultimately if you can avoid surgery too, then that’s really amazing. But we can’t draw that conclusion from this study yet. It’s going a little too far to say,” she said.

In a study involving over 100 patients, a dual-drug immunotherapy treatment shows impressive results in treating a specific form of colorectal cancer.

Mismatch repair-deficient (dMMR) colorectal cancer is found in 10-15% of all colorectal cancer cases and is characterized by a high number of genetic mutations.

These genetic mutations allow it to be more easily recognized by the immune system and make immunotherapy more likely to be effective.



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