MD Anderson researchers find mechanisms behind CAR-T cells’ efficacy, toxicity

The findings may make it possible to identify a subset of patients who experience poorer outcomes or more serious side effects, especially neurotoxicity.

While CAR-T cell therapies have greatly improved care for patients with diffuse large B-cell lymphoma, less than half of those who receive them experience long-term remissions, and many more experience serious and potentially fatal side effects. A newly published study based on a small number of DLBCL patients receiving one of the marketed CAR-Ts has provided some potential clues as to why that is.

Researchers at the University of Texas MD Anderson Cancer Center in Houston looked at data on 24 patients who had received Gilead Sciences’ Yescarta (axicabtagene ciloleucel) for DLBCL, and in particular at their T-cell counts and cell-free DNA sequencing. Yescarta is one of three CAR-Ts on the market – the other two are Novartis’ Kymriah (tisagenlecleucel) and Gilead’s Tecartus (brexucabtagene autoleucel). All three CAR-Ts work by targeting CD19, a protein found on the surfaces of cells in non-Hodgkin’s lymphomas and acute lymphoblastic leukemia. Results of the study were published in Nature Medicine.

In the years since Yescarta, Kymriah and other CAR-Ts entered the clinic – and the 2017 approvals of those two – oncologists have become much better at managing the toxicities associated with them, especially cytokine release syndrome, or CRS, and immune effector cell-associated neurotoxicity syndrome, or ICANS. Nevertheless, they remain problematic and often require patients to stay in the hospital after receiving CAR-Ts.

But the MD Anderson team has found data suggesting that it may be possible to identify a subset of patients who experience poorer outcomes or side effects, thereby enabling providers to adjust therapy to improve efficacy or mitigate toxicity.

“CAR-T cell therapy is highly effective against [large B-cell lymphoma],” corresponding study author Michael Green, an associate professor of lymphoma and myeloma at MD Anderson, said in a statement. “However, we experience two main clinical challenges: achieving long-term remission and managing treatment-associated adverse events.”

The researchers found that among patients who had achieved a complete response – as measured by PET/CT scans – frequencies of CD8 T cells expressing memory signatures were three times higher than among those patients who had achieved only partial responses or whose disease had progressed. Patients who showed molecular responses by cell-free DNA sequencing were more likely to have clinical responses, while exhaustion of CD8 T cells was associated with a poor molecular responses. Moreover, cell populations in the infusion product that had characteristics similar to those of myeloid cells were associated with patients developing high-grade ICANS.

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