CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors

Nat Commun. 2019 Sep 5;10(1):4016. doi: 10.1038/s41467-019-11869-4.

Abstract

Chimeric antigen receptor (CAR) T-cell therapy targeting solid tumors has stagnated as a result of tumor heterogeneity, immunosuppressive microenvironments, and inadequate intratumoral T cell trafficking and persistence. Early (≤3 days) intratumoral presentation of CAR T cells post-treatment is a superior predictor of survival than peripheral persistence. Therefore, we have co-opted IL-8 release from tumors to enhance intratumoral T-cell trafficking through a CAR design for maximal antitumor activity in solid tumors. Here, we demonstrate that IL-8 receptor, CXCR1 or CXCR2, modified CARs markedly enhance migration and persistence of T cells in the tumor, which induce complete tumor regression and long-lasting immunologic memory in pre-clinical models of aggressive tumors such as glioblastoma, ovarian and pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Glioblastoma / drug therapy
  • Glioblastoma / immunology*
  • Glioblastoma / pathology
  • Humans
  • Immunotherapy, Adoptive*
  • Interleukin-8 / metabolism*
  • Mice, Inbred NOD
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Interleukin-8A / metabolism*
  • Receptors, Interleukin-8B / metabolism*
  • T-Lymphocytes / immunology*
  • Tumor Microenvironment / immunology
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, Neoplasm
  • Cytokines
  • Interleukin-8
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B