Expression of a Functional CCR2 Receptor Enhances Tumor Localization and Tumor Eradication by Retargeted Human T Cells Expressing a Mesothelin-Specific Chimeric Antibody Receptor

Clin Cancer Res. 2011 Jul 15;17(14):4719-30. doi: 10.1158/1078-0432.CCR-11-0351. Epub 2011 May 24.

Abstract

Purpose: Adoptive T-cell immunotherapy with tumor infiltrating lymphocytes or genetically-modified T cells has yielded dramatic results in some cancers. However, T cells need to traffic properly into tumors to adequately exert therapeutic effects.

Experimental design: The chemokine CCL2 was highly secreted by malignant pleural mesotheliomas (MPM; a planned tumor target), but the corresponding chemokine receptor (CCR2) was minimally expressed on activated human T cells transduced with a chimeric antibody receptor (CAR) directed to the MPM tumor antigen mesothelin (mesoCAR T cells). The chemokine receptor CCR2b was thus transduced into mesoCAR T cells using a lentiviral vector, and the modified T cells were used to treat established mesothelin-expressing tumors.

Results: CCR2b transduction led to CCL2-induced calcium flux and increased transmigration, as well as augmentation of in vitro T-cell killing ability. A single intravenous injection of 20 million mesoCAR + CCR2b T cells into immunodeficient mice bearing large, established tumors (without any adjunct therapy) resulted in a 12.5-fold increase in T-cell tumor infiltration by day 5 compared with mesoCAR T cells. This was associated with significantly increased antitumor activity.

Conclusions: CAR T cells bearing a functional chemokine receptor can overcome the inadequate tumor localization that limits conventional CAR targeting strategies and can significantly improve antitumor efficacy in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Chemokines / biosynthesis
  • Cytotoxicity, Immunologic / immunology
  • GPI-Linked Proteins / immunology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mesothelioma / genetics
  • Mesothelioma / immunology
  • Mesothelioma / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Pleural Neoplasms / genetics
  • Pleural Neoplasms / immunology
  • Pleural Neoplasms / metabolism
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / immunology
  • Receptors, CCR2 / metabolism*
  • Receptors, Chemokine / immunology
  • Receptors, Chemokine / metabolism
  • Single-Chain Antibodies / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transduction, Genetic

Substances

  • Chemokines
  • GPI-Linked Proteins
  • Receptors, CCR2
  • Receptors, Chemokine
  • Single-Chain Antibodies
  • mesothelin