In a new study, researchers reported an association between immune dysregulation and failure with a chimeric antigen receptor (CAR) T-cell therapy in patients with large B-cell lymphoma (LBCL). Study results were published in the journal Blood.

A total of 105 patients with LBCL were evaluated in this prospective study examining factors that may be linked to durable response to axicabtagene ciloleucel (axi-cel), a CAR T therapy. Durable response was defined as remaining in remission for at least 6 months following axi-cel treatment. The study involved examinations of multiple features, such as tumor gene expression profiles, levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and other analyses.

The researchers found that patients without durable responses (NDR) more often showed significantly higher expression of genes that are considered to be targets of tumor interferon (IFN) signaling, compared with patients who had a durable response (DR).


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Higher percentages of positivity for programmed cell death-ligand 1 (PD-L1) and major histocompatibility complex II (MHCII) were seen in tumor cells of patients with NDR, compared with levels in patients with DR (P =.03 for PD-L1 and P =.02 for MHCII). Patients with NDR also showed a greater abundance of M-MDSCs at baseline than patients with DR did (P =.049).

Median peak axi-cel levels were 10 times higher in DR patients than in patients with NDR (P =.01), but they were 4 times lower in patients who had high levels of M-MDSCs at baseline (P =.02). Elevated expression of IFN signaling genes in the tumor microenvironment was also associated with less axi-cel expansion.

Some markers of systemic inflammation, such as ferritin, C-reactive protein, and interleukin-6 levels, were reportedly linked to poorer outcomes with axi-cel. Metabolic tumor volume additionally showed associations with several inflammatory markers measured at baseline and an association with increased tumor IFN signaling; past research had shown that increased metabolic tumor volume was linked to worse axi-cel response.

“In summary, our observations support that immune dysregulation is associated with resistance to CAR T-cell therapy in patients with LBCL,” the researchers wrote in their report. The researchers considered this immune dysregulation to be marked by high levels of circulating cytokines, M-MDSCs, and tumor IFN signaling. They also indicated that immune dysregulation could potentially be modified to limit relapses following CAR T treatment.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Jain MD, Zhao H, Wang X, et al. Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma. Blood. 2021;137(19):2621-2633. doi:10.1182/blood.2020007445