Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies
Anton Dobrin, Pieter L. Lindenbergh, Yuzhe Shi, Karlo Perica, Hongyao Xie, Nayan Jain, Andrew Chow, Jedd D. Wolchok, Taha Merghoub, Michel Sadelain, Mohamad Hamieh
Abstract
Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes. Furthermore, 80BB serves as a switch receptor that provides agonistic 4-1BB co-stimulation upon its ligation by the inhibitory CTLA4 molecule. By combining multiple co-stimulatory features in a single antigen-agnostic synthetic receptor, 80BB is a promising tool to sustain CD3-dependent T cell responses in a wide range of targeted immunotherapies. Dobrin et al. develop a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, which engages the CD28 and 4-1BB pathways and increases the antitumor potency of HLA-independent (HIT) and TCR-engineered T cells.