Reviving tired T cells when immuno-oncology drugs fail

Keytruda Opdivo
A new discovery may point the way toward making PD-1 checkpoint inhibitors like Keytruda and Opdivo effective for more patients.

Checkpoint inhibitors like Merck’s Keytruda (pembrolizumab) are designed to stimulate the immune system’s T cells to recognize and attack cancer cells. Problem is, they don’t work for many patients, and no one has been able to pinpoint exactly why that is. Now scientists at Emory say they’ve found a clue, in an immune protein called CD28.

Keytruda works by blocking the immune-suppressing protein PD-1, as does Bristol Myers-Squibb’s Opdivo (nivolumab). The drugs are now used to treat some types of melanoma, lung cancer and other tumors. But scientists from the Emory Vaccine Center and Winship Cancer Institute have published a paper demonstrating that even after PD-1 is blocked, cancer-killing T cells need additional “fuel” to proliferate and launch an immune response, according to a press release.

Stimulating CD28, which sits on the surface of T cells, could be the answer, the scientists say. In mouse experiments, they showed that when they used genetic engineering to delete CD28 or blocked it with antibodies, T cells were unable to expand in response to PD-1 inhibitors.

The team wanted to see what the ramifications of their findings would be for people, so they linked up with oncologists at Winship to analyze tissue samples taken from lung cancer patients treated with PD-1 inhibitors. They found that there was a wide range in the proportion of CD28-positive cells found among the T cells that infiltrated the tumors—20% to 90%. That shows that only a subset of T cells are primed to proliferate in response to PD-1 inhibition. The results were published online in the journal Science.

The search for more effective ways to block immune checkpoints is a priority for many biopharma companies. Because the FDA-approved checkpoint inhibitors have proven to work in only small subsets of patients, several companies have embarked on trials that combine the drugs with other immune-focused treatments. Opdivo is being tested in several combination trials, including one in lung cancer that pairs it with Johnson & Johnson’s JNJ-64041757, an experimental drug that uses an attenuated version of Listeria monocytogenes to stimulate an immune response. And Keytruda is being tested in melanoma alongside Amgen’s Imlygic, an “oncolytic” treatment derived from herpes virus.

The Emory-led team is now evaluating potential methods for using CD28 to improve immuno-oncology approaches. "Our study sets the stage to evaluate CD28 as a predictive biomarker for patient selection for immune checkpoint inhibition in patients with cancer,” says Suresh Ramalingam, M.D., deputy director of Winship, in the release, “and also paves the way for combination therapy approaches that might result in enhanced effectiveness of immune checkpoint inhibition."