IL-18-secreting CAR T-cells and antigen-low myeloma
Ng BD, Rajagopalan A, Kousa AI, et al. IL-18-Secreting Multi-Antigen Targeting CAR T-Cells Eliminate Antigen-Low Myeloma in an Immunocompetent Mouse Model. Blood. 2024; (doi: 10.1182/blood.2023022293).
Researchers have discovered that, by designing chimeric antigen receptor (CAR) T cells to secrete interleukin-18 (IL-18) and by also directing them at dual targets, they can achieve greater clearance of myeloma characterized by weak antigen expression. Low levels of B-cell maturation antigen (BCMA) on myeloma cells can undermine BCMA-directed CAR T therapy in this patient population, where it has otherwise shown great promise recently. Identifying a better way to manage antigen-low disease, investigators theorized, might generate better patient outcomes. Working in a syngeneic mouse model of myeloma, they found that CAR T cells targeting BCMA and B-cell activating factor (BAFF-R) were unable to eradicate myeloma when those antigens were weakly expressed. The opposite effect was observed when the cells were engineered to secrete IL-18, a pro-inflammatory cytokine. Those CAR cells developed an effector-like T-cell phenotype, stimulated interferon-gamma production, and activated macrophages to encourage anti-myeloma activity. Programming the cells to simultaneously seek out weakly expressed BCMA and BAFF-R boosted T-cell target avidity, raised engineered IL-18 output, increased overall CAR signal strength, and mediated anti-myeloma activity.