Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies. Academic Article uri icon

Overview

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.

publication date

  • March 19, 2024

Research

keywords

  • CD28 Antigens
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • Tumor Necrosis Factor Receptor Superfamily, Member 9

Identity

Digital Object Identifier (DOI)

  • 10.1038/s43018-024-00744-x

PubMed ID

  • 38503896