Xie et al. developed CAR T cells using variable regions of heavy-chain-only antibodies (VHHs) to target solid tumors. PD-L1-targeting CAR T cells generated from PD-L1-/- T cells slowed B16 or MC38 tumor growth and increased survival in PD-L1-/- immunocompetent mice. Generating PD-L1-targeted CAR T cells in the presence of PD-L1-blocking VHH prevented early activation and exhaustion, and improved the antitumor response. CAR T cells targeting EIIIB (a splice variant of fibronectin expressed specifically in the stroma and neovasculature of some tumors) delayed B16 tumor growth, increased T cell infiltration, and improved survival in WT mice.
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.
Author Info: (1) Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge
Author Info: (1) Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02138. (2) Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114. (3) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138. (4) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215. (5) Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115. (6) Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115. (7) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02138. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138. (8) Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02138. (9) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138. (10) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA Howard Hughes Medical Institute, Chevy Chase, MD 20815. (11) Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115; hidde.ploegh@childrens.harvard.edu.
