Chimeric antigen receptors with human scFvs preferentially induce T cell anti-tumor activity against tumors with high B7H6 expression

Cancer Immunol Immunother. 2018 May;67(5):749-759. doi: 10.1007/s00262-018-2124-1. Epub 2018 Feb 16.

Abstract

B7H6 is emerging as a promising tumor antigen that is known to be expressed on a wide array of tumors and is reported to stimulate anti-tumor responses from the immune system. As such, B7H6 presents a good target for tumor-specific immunotherapies. B7H6-specific chimeric antigen receptors (CAR) based on a murine antibody showed successful targeting and elimination of tumors expressing B7H6. However, mouse single chain variable fragments (scFvs) have the potential to induce host anti-CAR responses that may limit efficacy, so human scFvs specific for B7H6 were selected by yeast surface display. In this study, we validate the functionality of these human scFvs when formatted into chimeric antigen receptors. The data indicate that T cells expressing these B7H6-specific human scFvs as CARs induced potent anti-tumor activity in vitro and in vivo against tumors expressing high amounts of B7H6. Importantly, these human scFv-based CARs are sensitive to changes in B7H6 expression which may potentially spare non-tumor cells that express B7H6 and provides the foundation for future clinical development.

Keywords: Affinity; Immunotherapy; Lymphoma; Single-chain variable fragment.

MeSH terms

  • Animals
  • B7 Antigens / immunology*
  • Female
  • Humans
  • Immunotherapy*
  • Lymphoma / immunology*
  • Lymphoma / metabolism
  • Lymphoma / therapy
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Chimeric Antigen / immunology*
  • Single-Chain Antibodies / immunology*
  • T-Lymphocytes / immunology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • B7 Antigens
  • B7-H6 antigen, human
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • Single-Chain Antibodies