Title: Immune Therapy First to Show Activity in Common Colon Cancer
Abstract: colon cancer: colon cancerWhile immunotherapies have improved outcomes for patients with a number of different cancers in recent years, that hasn't been the case for patients with metastatic microsatellite stable (MSS) colon cancer, the most common type of the disease. Now, researchers at Dana-Farber Cancer Institute report the results of a new immune therapy using two novel drugs that is the very first to show activity in patients with MSS colon cancer. Data from the expanded Phase Ia/Ib clinical trial were presented at the 2023 ASCO Gastrointestinal Cancers Symposium. The study included 70 patients with metastatic MSS colorectal cancer previously heavily treated with one or more drug lines, including immune therapies. At a median follow-up of 7 months, 23 percent of patients, had significant tumor reduction and 76 percent had stable disease or better. At 1 year, the overall survival rate was 63 percent, although patients with cancer metastasized to the liver did not do as well. Treatment-related adverse events were common, occurring in 91 percent of patients, with 40 percent having a Grade 3 event and 3 percent having a Grade 4 event. Among all patients, 12 percent discontinued the trial due to these adverse events. “This is the first immune therapy—the first checkpoint inhibitor—to work in any form in the most common type of advanced colon cancer,” said the study's lead author, Benjamin L. Schlechter, MD, Senior Physician in the Gastrointestinal Cancer Treatment Center at Dana-Farber and Instructor in Medicine at Harvard Medical School.Benjamin L. Schlechter, MD: Benjamin L. Schlechter, MDBoth drugs are second-generation antibody immune therapies. One part of the combination, balstilimab, prevents the immune checkpoint protein PD-1 from interacting with PD-L1 and PD-L2. Botensilimab is a second-generation checkpoint inhibitor that targets the T-cell receptor and immune checkpoint regulating T-cell activation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and appears to be the main driver of responses. Research is underway to determine the best combination of these agents. “The change that was made in immune checkpoint regulating CTLA-4 was to allow it to interact with a different cell in the immune system called a natural killer cell (NK) and to improve the activation of those cells based on the observation that NK cells seem to help,” Schlechter said. “The other thing that was done was the alteration made in the molecule to prevent them from interacting with another part of the immune system called the complement system. By reducing complement activating and increasing NK cell activation, the hope was that it would improve the efficacy of the treatment—and it worked.” Schlechter noted that the Phase I study also shows that where colorectal cancer metastasizes predicts response. “We had known for a while that different parts of the body interact with cancer in different ways, and this was really brought home with the clinical trial where patients with cancer outside of the liver did better.” Eliciting a Response Previous studies found immunotherapies were effective in very rare microsatellite-unstable (MSI) colorectal cancer tumors. However, only 3-5 percent of advanced colorectal tumors are MSI, and there are no FDA-approved immunotherapies for MSS colon cancer. “One of the challenges in treating common colon cancer has been the significant lack of benefit from immunotherapy, and a lot of effort has gone into trying to figure out why and to try to find new forms of immune therapy,” Schlechter said. So when a friend and former colleague sought to collaborate on new research looking at altering the way immune therapies interact with each other to potentially overcome resistance in colon cancer, he was happy to help. “One of the benefits of being at Dana-Farber is that we have a lot of patients and a lot of experience with research. Plus, they had a really great idea,” Schlechter noted. “And so it was actually a case of good science and good friends collaborating at the right time. “The immune system is very carefully orchestrated with a lot of cells that upregulate and downregulate as part of a complex reaction to deal with trouble. There's enough of a reaction to kill off infection, but without so much of a response that you get sick,” he continued. “And so these drugs very clearly alter that balance and promote inflammation in a way that helps fight cancer, but also promotes inflammation in a way that we need to be very, very careful about.” While many patients had side effects in the new study, all of them were manageable and there was nothing untreatable. “There's a very pronounced amount of random immune activation that we have gotten very good at treating,” Schlechter said. “ I think, in the beginning, that was actually very surprising, both how effective this was and how quickly this could cause problems if you don't take care of people carefully.” ‘A Very Different Compound’ So many existing immune therapies have been trialed and failed in advanced colon cancer that some may find it hard to believe something new actually worked, Schlechter conceded. “But I think it would be a mistake to think of this drug as just another member of the checkpoint inhibitor class,” he said. “Whether you call it a new class or a second-generation checkpoint inhibitor, this is a different drug than the existing ones. I think that is borne out in the behavior of the side effects and in the efficacy of the drug in colon cancer. It's a very different compound.” The side effect profile of patients in the trial was not “unexpected,” Schlechter noted, but it was “interesting.” There were no side effects or adverse events previously unseen with existing immune therapies. “The other checkpoint inhibitors do all of the same things that these drugs do, but they do them in different proportions.” While rates of colitis were higher in the Phase I study compared to first-generation immune therapies, there also was a decrease in an injury to the pituitary gland in the brain. “That was hypothesized to be the case based on the mechanisms of the changes that were made to these drugs. And it turns out to be true,” he said. Anatomy & the Immune Environment It also would be a mistake to underestimate the importance of anatomy in the immune environment, Schlechter noted. “Ten years ago, we wouldn't have known to look for these problems. But we are now beginning to look for those things routinely. And, hopefully, over the next few years, we can even explain why cancer behaves differently in certain organs,” he said. The immune system deals with problems differently than chemotherapy, Schlechter explained. “Chemotherapy goes everywhere and in the same way, transported by the blood supply. But the immune system is different. As your body heals and grows, your immune system reacts to inflammation and it has to manage inflammation in unique ways throughout the body.” The immune environment of different organs may also help to explain why common MSS colon cancer has been resistant to immune therapies, Schlechter said, offering a comparison of the lungs and liver. “Your lung is an area of your body that has a tremendous amount of immune activation. You inhale dirt and viruses and the immune system jumps right in so that you're not sick all the time. And so the innate immunity inside your lungs is probably better than other parts of your body, like the liver, for example.” Although it serves a similar function to the lungs in terms of sifting dirt and processing other contaminants, “the liver must not overreact,” Schlechter said. “The liver needs to be suppressed in a very limited environment so that you are not constantly getting sick from everything you eat. And that means that cancer may have an advantage growing in the liver because of that chronic immune suppression. When you take a chronically immune-suppressed malignancy like colon cancer and put it into an environment that also is chronically immune-suppressed, like the liver, you get a really dangerous combination.” The Next Big Things Based on the results of the Phase I study, Dana-Farber researchers are launching two new Phase II trials of these drugs. The first Phase II trial is a randomized study to determine the best combination and dose. Eighty percent of patients will receive the novel drugs in different doses and combinations while 20 percent get chemotherapy. In the other Phase II study, all patients will get the same combination and dose of the immune therapy. Two-thirds of the patients will also receive the anti-inflammatory drug before they experience side effects, while the rest will be treated after they get sick to determine the best time to administer anti-inflammatory treatment. “Cancer medicine is riddled with good ideas. For better or worse, most good ideas don't make good medicine,” said Schlechter, reflecting on the monumental progress seen in the ongoing research and the hope it offers patients with common colon cancer. “But this is an example of where a good idea ends up making good medicine, and that's really, really encouraging,” he said. “We always go into each clinical trial hoping that we've got a winner. Only, most clinical trials aren't successful. So it is very gratifying to see the behavior of the drug in people work out.” Chuck Holt is a contributing writer. Top 10 Best Hospitals for Cancer