Checkpoint inhibitors like Merck’s blockbuster PD-1 blocker Keytruda are now widely used to treat several tumor types, but many patients don’t respond to these drugs for reasons that remain a mystery. Now, a team led by researchers at the University of Pittsburgh School of Medicine is shedding new light on a possible mechanism of resistance to PD-1 blockade.
The researchers found a correlation between the expression of the cell-surface protein LAG-3 and another protein called ADAM-10, which normally regulates LAG-3 signaling. They found that high amounts of LAG-3 coupled with low levels of ADAM-10 were correlated with resistance to anti-PD-1 drugs in patients with head and neck squamous cell carcinoma and some skin cancers. They reported the finding in the journal Science Immunology.
LAG-3 is already a target in oncology drug development because of the earlier discovery that the success of checkpoint blockade hinges on the ability of the protein to be “cleaved” from the surface of T cells. At least 10 LAG-3-targeted drugs are currently in clinical trials.
The University of Pittsburgh team engineered a form of LAG-3 that can’t be cleaved and tested it in mouse models of cancer. They found that the animals were resistant to anti-PD-1 therapy.
In separate experiments, they studied anti-PD-1 responsiveness in mouse models. They found that if LAG-3 shedding was driven by “helper” T cells rather than the more famous “killer” T cells, the mice were more responsive to PD-1 blockade.
The researchers believe that their findings suggest “that LAG-3 acts as a mechanism of primary resistance in patients with advanced cancer receiving checkpoint blockade therapy,” and that high LAG-3 expression coupled with low amounts of ADAM-10 might be a biomarker of poor response to PD-1 blockade, they wrote in the study. They also suggested that helper T cells could be a target in ongoing efforts to improve responses to checkpoint inhibition.
Several companies are pursuing LAG-3 inhibition in cancer, including F-star, which turned in promising preclinical data suggesting that a bispecific drug targeting both LAG-3 and PD-L1 can overcome resistance to immuno-oncology drugs. Merck KGaA walked away from a development partnership with F-star last year, but the company is forging ahead and has said it could release phase 1 data this year.
Merck & Co. also has a LAG-3 program. In 2018, it released data showing that its anti-LAG-3 drug MK-4280 combined with Keytruda produced a partial response in 27% of patients with metastatic solid tumors in a phase 1/2 study. The disease control rate was 40% for the combo.
With therapies such as these advancing through clinical trials, “a better understanding of the role of LAG-3 inhibitory signaling in the targeted immune cell network becomes critical,” wrote researchers from University Medical Center Freiburg in German in commentary that accompanied the University of Pittsburgh study. “Comprehensive monitoring of immune cell activation and function will be required” to enhance these trials going forward, they added.