Myeloid Cells’ Inhibition of IL-1 Signaling Bolsters MCL Resistance to CAR T-Cell Therapy

A team of researchers has investigated the role of myeloid cells in mantle cell lymphoma (MCL) cells’ development of resistance to CD19-directed chimeric antigen receptor (CAR) T-cell therapies. The team’s findings were presented at the 66^th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

“Our study elucidates a potential mechanism of [Interleukin-1 (IL-1)] pathway modulation mediated by myeloid cells in contributing to [CD19-directed CAR T-cell therapy] failure in MCL,” wrote Kun Yun, BS, MSc, of Mayo Clinic in Rochester, Minnesota.

Their investigation began with a single-cell RNA sequencing analysis of brexucabtagene autoleucel (brexu-cel) products generated from patients in the ZUMA-2 clinical trial and transcriptomic analyses of the patients’ autologous baseline monocyte populations. The results from these initial analyses suggested that myeloid cells hinder IL-1 signaling in brexu-cel products, leading to MCL cell resistance to this therapy.

Next, in preclinical models, the researchers cocultured CD19-directed CAR T-cell therapy cells from healthy donors with a CD19-positive MCL cell line, along with ex vivo differentiated M2-like macrophages or freshly isolated monocytes. They observed that the M2-like macrophages, but not the monocytes, markedly inhibited antigen-specific proliferation of the CAR T-cells. This effect from the M2-like macrophages appeared to be from their secretion of IL-1 receptor antagonist (IL-1ra), which blocked IL-1 signaling in the therapy.

To examine this possible driver of impeded therapy efficacy, the investigators made cocultures of CD19-directed CAR T-cells and a CD19-positive MCL cell line and then applied to them IL-1β plus IL-1ra or IL-1β plus IL-1ra and IL-1ra neutralizing antibody (neuAb). They found that IL-1β improved CAR T-cell proliferation, IL-1ra inhibited this proliferation, and that neutralization of IL-1ra then restored proliferation.

For the final step of their investigation, the researchers observed in mouse MCL xenografts how IL-1ra affected CD19-directed CAR T-cell therapy activity in the midst of M2-like macrophages. On bioluminescence imaging, they saw that combining CAR T-cells with IL-1ra neuAb brought stronger antitumor activity. They also noticed that the M2-like macrophages caused downregulated expression of a particular receptor for IL-1β and IL-1ra on CAR T-cells, possibly impeding the cells’ proliferation.

Reference

Yun K, Sakemura RL, Can I, et al. Intrinsic immunosuppressive features of monocytes suppress CART19 through IL-1 pathway modulation in mantle cell lymphoma. Abstract #908. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024; San Diego, California.