Journal Article

In situ PEGylation of CAR T cells alleviates cytokine release syndrome and neurotoxicity

Mitchell, Michael J, El-Mayta, Rakan, Hamilton, Alex G, Metzloff, Ann E, Billingsley, Margaret M, Han, Xuexiang, Gong, Ningqiang, Xue, Lulu

2023

Overview

Chimeric antigen receptor T (CAR T) cell immunotherapy is successful at treating many cancers. However, it often induces life-threatening cytokine release syndrome (CRS) and neurotoxicity. Here, we show that in situ conjugation of polyethylene glycol (PEG) to the surface of CAR T cells (‘PEGylation’) creates a polymeric spacer that blocks cell-to-cell interactions between CAR T cells, tumour cells and monocytes. Such blockage hinders intensive tumour lysing and monocyte activation by CAR T cells and, consequently, decreases the secretion of toxic cytokines and alleviates CRS-related symptoms. Over time, the slow expansion of CAR T cells decreases PEG surface density and restores CAR T cell–tumour-cell interactions to induce potent tumour killing. This occurs before the restoration of CAR T cell–monocyte interactions, opening a therapeutic window for tumour killing by CAR T cells before monocyte overactivation. Lethal neurotoxicity is also lower when compared with treatment with the therapeutic antibody tocilizumab, demonstrating that in situ PEGylation of CAR T cells provides a materials-based strategy for safer cellular immunotherapy.Polyethylene glycol conjugation to chimeric antigen receptor T (CAR T) cells creates a physical block between CAR T cell interactions and other immune and tumour cells, controlling tumour lysis and immune response stimulation to mitigate cytokine release syndrome.

• Publisher: Nature Publishing Group
• Subject: Antibodies / Antigens / Conjugation / Cytokines / Immune response / Immune system / Immunotherapy / Lymphocytes / Monoclonal antibodies / Neurotoxicity / Polyethylene glycol / Receptors / Tumors