CAR T Signaling Differences Could Point the Way to More Targeted Treatments, Study Says

The first chimeric antigen receptor (CAR) T-cell therapy was approved just a year ago, changing the face of treatment for certain types of leukemias and lymphomas but carrying with it the downsides of toxicity and cost. A year later, scientists from a major cancer center said that they’ve made headway to discovering more about the T-cell signaling patterns and that understanding more about the biological pathways could help design the next generation of CAR-T treatments.

Such treatments could have reduced adverse events, a lower rate of posttreatment relapse, or the ability to work against solid tumors.

Researchers at Fred Hutchinson Cancer Research Center published their study in Science Signaling. Their work compared T-cell signaling patterns in 2 different CAR designs and found that the differences between them could mean some might work better on some cancers and some might be more effective on others.

In a statement, the researchers said their findings do not mean that one is superior to another. But the results “do support clinical observations for how CARs work in patients and give insights on why some patients experience stronger side effects from CAR T and why some relapse following treatment.”

There are 2 CAR T treatments on the market: tisagenlecleucel (Kymriah)—a treatment for children and young adults with B-cell acute lymphoblastic leukemia developed by Novartis—and axicabtagene ciloleucel (Yescarta)—Kite Pharma/Gilead’s treatment for adult patients with relapsed or refractory large B-cell lymphoma.

The 2 CAR designs, called CD28 and 4-1BB, signaled their T cells differently. Both CAR variants modified proteins in nearly identical ways. But in a mouse model, the CAR T cells with stronger signaling capabilities (the CD28 cells) are counterintuitively less effective at killing lymphoma cells in a mouse model.

The study also found that a signaling protein in T cells called Lck modulates the intensity of the T cell response in the CD28 CAR design, and the researchers could manipulate it to finetune the response of the CD28 CAR.

Also, 4-1BB CAR T cells showed greater expression of genes associated with T-cell memory, which suggests that the 4-1BB CAR signaling may give rise to T cells that can live longer and maintain their anticancer effects.

Modulating the strength of CAR receptors could help optimize therapies by increasing their efficacy or reducing treatment toxicity, the study suggests.

One of the potential adverse events of CAR T, cytokine-release syndrome, can range from high fevers to potentially life-threatening complications requiring care in an intensive care unit.

"Our results suggest how different CAR designs could be used for different purposes," said Alexander Salter, who was a graduate student during the study. "The faster, stronger response of the CD28 CAR might benefit certain cancers whereas the slower, longer-lasting 4-1BB CAR could benefit others."

Reference

Salter AI, Ivey RG, Kennedy JJ, et al. Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function [published online August 21, 2018]. Sci. Signal. doi: 10.1126/scisignal.aat6753.