In trial after clinical trial, metastatic colorectal cancer has been largely undeterred by immune checkpoint inhibitors. 

Although these drugs have shown effectiveness in Hodgkin lymphoma, lung cancer, bladder cancer, kidney cancer, and nearly a dozen other malignancies, their track record against colorectal cancer has been lackluster, particularly for patients with the most common subtype of the disease, known as microsatellite stable (MSS). Researchers have tested checkpoint inhibitors alone and in pairs, with chemotherapy and without, with similar, unimpressive results. 

In a recent clinical trial, however, a combination of checkpoint inhibitors – one new, one a standard agent – benefited nearly 75% of patients with MSS metastatic colorectal cancer that was resistant to chemotherapy and had not spread to the liver. The results, published in Nature Medicine, make the regimen the first immunotherapy to prove safe and effective in this group of patients.   

The new agent, botensilimab, is not a radically new kind of checkpoint inhibitor, but a modified version of existing inhibitors that target the CTLA-4 protein on immune system T cells. Its success in the trial is an example of how “a small tweak in a known pathway can make a big difference in patients,” says Dana-Farber’s Benjamin L. Schlechter, MD, who co-led the study. 

Making repairs 

MSS colorectal cancer, which accounts for 95-97% of colorectal cancer cases, is able to repair certain types of errors in the DNA of tumor cells. The ability to keep its genomic house in order helps MSS colorectal cancers dodge the effects of immune checkpoint inhibitors. 

Checkpoint inhibitors work by exposing cancer cells to an immune system attack. The drugs target special proteins on tumor cells or T cells that place a restraining order on the immune system, causing it to leave cancer cells unharmed. By blocking those proteins, checkpoint inhibitors lift the restraining order and allow the attack on cancer to commence. 

Like all forms of immunotherapy, checkpoint inhibitors are only as effective as the immune system’s ability to find cancer cells and eliminate them. It is here that MSS colorectal cancer’s ability to fix faulty DNA gives it an advantage over other, less fastidious colorectal cancers, known as microsatellite instability high (MSI-H). 

Schlechter explains: “Because MSI-H colorectal cancers have a large number of genetic mutations, it’s relatively easy for the immune system to find abnormalities on tumor cells that it can latch onto and attack. The more normal-appearing nature of MSS cancers, however, makes them less visible to the immune system.  As a result, MSS tumors don’t respond as well to immunotherapy.” 

Botensilimab is designed to overcome these obstacles in two ways. First, it binds tightly to the CTLA-4 checkpoint inhibitor on T cells within the tumor, making them especially active against cancer. Second, it spurs a broader mix of immune system cells to join the fight against cancer than conventional CTLA-4 inhibitors do. 

“It recruits cells that are especially effective against cancer and doesn’t recruit certain proteins that can have adverse effects,” Schlechter remarks.  

Specifically, it doesn’t recruit a group of proteins known as the complement factor system, which help defend against infections but are thought to be responsible for some of the side effects of cancer immunotherapy. On the plus side, the drug not only unleashes a T cell attack on cancer – as other CTLA-4 inhibitors do – but also enlists other immune system cells, called natural killer (NK) cells, as reinforcements. 

“The area around a tumor is often immunosuppressive – it dampens the strength of the immune response,” Schlechter relates. “By recruiting NK cells to the area, Botensilimab actually changes that environment to one that’s more conducive to an immune attack.” 

Unprecedented results 

In the trial, a phase I study, 142 patients with MSS metastatic colorectal cancer resistant to chemotherapy were treated with a combination of botensilimab and balstilimab, which targets the PD-1 checkpoint protein on T cells. Investigators found that 73% of participants whose cancer hadn’t spread to their liver benefited from the treatment and nearly a quarter had a major response, including the disappearance of their metastatic growths. 

These results, coming after multiple clinical trials in which checkpoint inhibitors had shown little effect against metastatic colorectal cancer, may well mark a turning point against the disease. “Our findings are really quite impressive, especially given that many participants had undergone multiple previous treatments,” Schlechter remarks.  “The results were better than I’d expected. I’ve never said that before about an investigational drug.” 

With the success of the phase I trial, Schlechter is now leading a phase III trial of the botensilimab/balstilimab combination in patients. 

Learn more about colorectal cancer from Dana-Farber Cancer Institute.

About the Medical Reviewer

Dr. Schlechter is a medical oncologist who specializes in gastrointestinal cancers including colorectal cancer, anal cancer, pancreatic cancer, and neuroendocrine cancers, among others. He is a former intern, resident, chief resident and fellow at Beth Israel Deaconess Medical Center as well as a member of the faculty at Harvard Medical School. In the past he was the Director of Inpatient Hematology and Oncology at Beth Israel Deaconess Medical Center as well as the Assistant Program Director of the Internal Medicine Residency Program. His work at Dana-Farber focuses on providing excellent patient care while trying to advance the treatment of gastrointestinal cancer patients.