Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2 + Breast Cancer Metastasis to the Brain

Clin Cancer Res. 2018 Jan 1;24(1):95-105. doi: 10.1158/1078-0432.CCR-17-2041. Epub 2017 Oct 23.

Abstract

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease.Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain.Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease.Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / secondary*
  • Brain Neoplasms / therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • CD28 Antigens / genetics
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Female
  • Humans
  • Immunotherapy, Adoptive* / methods
  • Inflammation Mediators / metabolism
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Receptor, ErbB-2 / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
  • Xenograft Model Antitumor Assays

Substances

  • CD28 Antigens
  • Cytokines
  • Inflammation Mediators
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Receptor, ErbB-2