Apr 3, 2019

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

Proceedings of the National Academy of Sciences of the United States of America
Yushu Joy XieHidde Ploegh

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...Continue Reading

  • References1
  • Citations12

References

  • References1
  • Citations12

Mentioned in this Paper

Immune Response
Antineoplastic Agents
T-Lymphocyte
Hematologic Neoplasms
Splice Variants, Protein
Gastrointestinal Stromal Tumors
Neoplasms
Multiple Malignancy
Programmed Cell Death Protein 1
Pharmacologic Substance

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