Bispecific CAR T Cells against EpCAM and Inducible ICAM-1 Overcome Antigen Heterogeneity and Generate Superior Antitumor Responses. Academic Article uri icon

Overview

abstract

  • Adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated unparalleled responses in hematologic cancers, yet antigen escape and tumor relapse occur frequently. CAR T-cell therapy for patients with solid tumors faces even greater challenges due to the immunosuppressive tumor environment and antigen heterogeneity. Here, we developed a bispecific CAR to simultaneously target epithelial cell adhesion molecule (EpCAM) and intercellular adhesion molecule 1 (ICAM-1) to overcome antigen escape and to improve the durability of tumor responses. ICAM-1 is an adhesion molecule inducible by inflammatory cytokines and elevated in many types of tumors. Our study demonstrates superior efficacy of bispecific CAR T cells compared with CAR T cells targeting a single primary antigen. Bispecific CAR T achieved more durable antitumor responses in tumor models with either homogenous or heterogenous expression of EpCAM. We also showed that the activation of CAR T cells against EpCAM in tumors led to upregulation of ICAM-1, which rendered tumors more susceptible to ICAM-1 targeting by bispecific CAR T cells. Our strategy of additional targeting of ICAM-1 may have broad applications in augmenting the activity of CAR T cells against primary tumor antigens that are prone to antigen loss or downregulation.

publication date

  • August 2, 2021

Research

keywords

  • Epithelial Cell Adhesion Molecule
  • Immunotherapy, Adoptive
  • Intercellular Adhesion Molecule-1
  • Neoplasms
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen

Identity

PubMed Central ID

  • PMC8492509

Scopus Document Identifier

  • 85118097292

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-21-0062

PubMed ID

  • 34341066

Additional Document Info

volume

  • 9

issue

  • 10