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Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7624-7631. doi: 10.1073/pnas.1817147116. Epub 2019 Apr 1.

Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice.

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
2
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02138.
3
Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114.
4
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138.
5
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215.
6
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02138.
7
Howard Hughes Medical Institute, Chevy Chase, MD 20815.
8
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115; hidde.ploegh@childrens.harvard.edu.

Abstract

Chimeric antigen receptor (CAR) T cell therapy has been successful in clinical trials against hematological cancers, but has experienced challenges in the treatment of solid tumors. One of the main difficulties lies in a paucity of tumor-specific targets that can serve as CAR recognition domains. We therefore focused on developing VHH-based, single-domain antibody (nanobody) CAR T cells that target aspects of the tumor microenvironment conserved across multiple cancer types. Many solid tumors evade immune recognition through expression of checkpoint molecules, such as PD-L1, that down-regulate the immune response. We therefore targeted CAR T cells to the tumor microenvironment via the checkpoint inhibitor PD-L1 and observed a reduction in tumor growth, resulting in improved survival. CAR T cells that target the tumor stroma and vasculature through the EIIIB+ fibronectin splice variant, which is expressed by multiple tumor types and on neovasculature, are likewise effective in delaying tumor growth. VHH-based CAR T cells can thus function as antitumor agents for multiple targets in syngeneic, immunocompetent animal models. Our results demonstrate the flexibility of VHH-based CAR T cells and the potential of CAR T cells to target the tumor microenvironment and treat solid tumors.

KEYWORDS:

chimeric antigen receptor; immunotherapy; tumor microenvironment

PMID:
30936321
DOI:
10.1073/pnas.1817147116

Conflict of interest statement

The authors declare no conflict of interest.

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