The emerging form of cancer treatment called CAR T immunotherapy is wiping out the disease in some terminal patients — but despite early successes, the treatments still have major drawbacks. Many patients who take CAR T treatment also battle dangerous side effects, which can be deadly. For some patients, the treatments simply don’t work at all.
But a new understanding of how CAR T immunotherapy works, gleaned from a study by researchers at Seattle’s Fred Hutchinson Cancer Research Center, points to redesigns that might eliminate those problems.
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The researchers initially wanted to understand why some CAR T treatments seemed to have different traits than others — for example, some kinds of treatments stay in a patient’s body longer.
To figure out what was causing the difference, researchers zeroed in on the relationship between the two parts of a CAR T treatment that make it work: A patient’s T-cells, immune cells that fight disease, and a man-made chimeric antigen receptor (CAR) that is spliced into those cells to make them find and destroy cancer. Those two components communicate through a process called signaling.
“What we’ve learned from this study is how these receptors are actually signaling,” said Dr. Stan Riddell, the leader of Fred Hutch’s immunotherapy research center, during a news conference this week. This area is not well understood, and the researchers’ results revealed “some new insights, surprising insights, and I think some real direction for future work,” Riddell said.
Along with Fred Hutch researcher and mass spectrometry expert Dr. Amanda Paulovich, researcher Alex Salter compared CAR T treatments that use two different molecules, called CD28 and 4-1BB.
Many of the current CAR T treatments, including the two CAR T treatments currently approved by the FDA, include these molecules and studies have shown that they impact how the treatments behave. Scientists thought this was because the molecules use different proteins when they are telling the T cells what to do, but it turns out that was not the case.
“Instead, the major difference between these receptors was that the speed and the strength of the signaling was different,” said Salter, an MD/PhD student in Riddell’s lab and the lead author of the study. “The CD28 CAR signaled faster and stronger,” while the CARs with 4-1 BB let out a slower, weaker signal.
Funnily enough, the faster and stronger signal did a worse job of attacking cancer when Salter compared the two in mice with lymphoma.
The fast and strong signaling treatment had a “very strong initial anti-tumor function, but this anti-tumor function quickly waned and the T-cells became exhausted,” Salter said. “In contrast, the slower burning, more gentle 4-1BB CAR signal led to T cells that better retained their function.”
Importantly, this difference in signaling could point to a solution for CAR T therapy’s side effects.
“It’s been known for a while that CD 28 will result in high levels of cytokines,” Riddell said, referring to a molecule that causes a severe side effect and may also lead to other side effects. “What our data really says is that the major reason for that is the rapidity and extent of the signaling.”
But the researchers didn’t stop there: Salter went on to design a modified CAR with CD28 that slowed down and weakened the molecule’s strong signal, potentially sidestepping unwanted effects and making the treatment more effective at fighting cancer.
“This is a modification we think should be considered in future CAR design,” he said.
Although the results are promising, this study is only the tip of the iceberg when it comes to fully understanding how CAR T signaling works. It’s possible further understanding of the science could fine-tune CAR T treatments as scientists work to make the treatments work for more people, including expanding them into solid tumor cancers like breast and lung cancer.
GeekWire’s Health Tech podcast tells the dramatic story of CAR T immunotherapy on a recent episode, featuring Dr. Stan Riddell and other leading researchers. Listen to the episode in the player below.