Suppression of cytokine release syndrome by conjugating TCR-signaling-responsive siltuximab nanogels with CAR-T cells

CAR-T cell therapy has demonstrated significant anti-tumor responses in hematological malignancies and even solid tumors. However, the overactivation of CAR-T cells <em>in vivo</em> can lead to cytokine release syndrome (CRS), with the unpredictable timing and severity of its onset making it difficult to manage effectively. In this study, a strategy was proposed to prevent and treat CAR-T cell-induced CRS <em>in situ</em> by conjugating T cell receptor (TCR)-signaling-responsive siltuximab nanogels (NGs) with CAR-T cells. These siltuximab NGs, formed <em>via</em> NHS-S-S-NHS cross-linking, non-covalently bind to CAR-T cells through anti-CD45, significantly prolonging NGs retention time <em>in vivo</em> while preserving the anti-tumor activity of CAR-T cells. Upon excessive activation of CAR-T cells during tumor therapy, the increased reductive environment on the T cell surface triggers the disassembly of siltuximab NGs, releasing siltuximab monomers to inhibit CRS <em>in situ</em>. In a CAR-T cell-mediated CRS mice model, CAR-T@NGs effectively alleviated CRS-related symptoms, such as high fever, weight loss, vascular leakage, coagulation dysfunction, and neurotoxicity. Furthermore, NGs administered <em>in vivo</em> did not cause organ damage and provided a safe and timely treatment for CRS.