Checkpoint inhibitors to treat cancers, such as Roche’s Tecentriq, have been hailed for their ability to free up the immune system to recognize and attack tumors. But the drugs fail to work in as many as 80% of patients—a problem that their manufacturers have been trying to solve, along with a bevy of academic oncology researchers.
Now Roche is uncovering data from a Tecentriq trial in bladder cancer patients that provides clues about what may be causing resistance to checkpoint inhibitors—and how that resistance might be countered. After analyzing data from 300 patients in the trial, researchers from Roche’s Genentech unit found two biomarkers that drive a good response to drugs that inhibit the checkpoint PD-L1, as Tecentriq does, and one that drives resistance. They announced their findings at the European Society for Medical Oncology (ESMO) conference in Geneva.
The culprit for resistance was a protein called TGF-beta, which was present in high levels in tumors of patients who did not respond well to Tecentriq. The researchers did some digging and found that in those patients, cancer-fighting T cells were either severely lacking, or they were stuck to a wall made of collagen that prevented them from getting inside cancer cells. Because high expression of TGF-beta was associated with non-responders to PD-L1 inhibition, they surmised the protein may be involved in building that wall.
Using a mouse model of cancer with low T-cell penetration, the researchers went on to examine whether inhibiting TGF-beta could enhance the efficacy of Tecentriq. It worked: A combination of the drug and an anti-TGF-beta compound allowed more T cells to get into the center of the tumor, reducing the size of the cancerous mass, according to a statement released at the ESMO event.
"This suggests that giving anti-TGF-β and anti-PD-L1 together can remodel the stromal microenvironment and allow T cells into the [tumor],” said Sanjeev Mariathasan, a senior scientist in the oncology biomarker department at Genentech, in the statement. He added that low levels of T-cell penetration are commonly seen in other tumor types, including pancreatic, lung and colon cancer—making a potential combination approach relevant to a wide audience of patients.
Several combination approaches to boosting immune checkpoint inhibitors are being studied. In September, researchers at Columbia University Medical Center tried combining checkpoints with pentoxifylline, a drug that’s currently used to improve blood circulation. They discovered that in mouse models of melanoma, the cocktail helped control the activity of regulatory T cells (Tregs) by preventing them from suppressing cancer-killing T cells. Separately, a group at Memorial Sloan Cancer Center in New York found that in animal trials, an inactivated formulation of vaccinia virus helped boost tumor-fighting T cells when given along with checkpoint inhibitors.
Some TGF-beta inhibitors are in clinical trials, though their record has been mixed so far. Acceleron’s TGF-targeting drug, sotatercept, is in a development pact with Celgene. But the prospects for the drug became less clear in September, when Acceleron took back the rights to develop it in pulmonary disease. Eli Lilly has been developing a TGF-beta inhibitor in cancer, but in July, it put the drug up for sale.
The most recent Roche research on Tecentriq argues in favor of the development of better TGF-beta-blockers, suggests Ignacio Melero, a senior researcher at the Centre for Applied Medical Research (CIMA) in Pamplona, Spain. “These molecules are in clinical trials but have not yielded remarkable success because of efficacy and safety constraints,” he said, adding that it might be valuable to use gene testing to identify the patients with high levels of TGF-beta “and focus on synergistic combinations," Melero said in the ESMO release.