Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor

Leukemia. 2017 Oct;31(10):2151-2160. doi: 10.1038/leu.2017.8. Epub 2017 Jan 12.

Abstract

The outlook for T-cell malignancies remain poor due to the lack of effective therapeutic options. Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies, however, designing CARs for T-cell based disease remain a challenge due to the shared surface antigen pool between normal and malignant T-cells. Normal T-cells express CD5 but NK (natural killer) cells do not, positioning NK cells as attractive cytotoxicity cells for CD5CAR design. Additionally, CD5 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCLs). Here, we report a robust anti-CD5 CAR (CD5CAR) transduced into a human NK cell line NK-92 that can undergo stable expansion ex vivo. We found that CD5CAR NK-92 cells possessed consistent, specific, and potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells. Furthermore, we were able to demonstrate significant inhibition and control of disease progression in xenograft mouse models of T-ALL. The data suggest that CAR redirected targeting for T-cell malignancies using NK cells may be a viable method for new and complementary therapeutic approaches that could improve the current outcome for patients.

MeSH terms

  • 4-1BB Ligand / genetics
  • 4-1BB Ligand / immunology
  • Animals
  • Antigens, Neoplasm / immunology*
  • CD28 Antigens / immunology
  • CD3 Complex / genetics
  • CD3 Complex / immunology
  • CD5 Antigens / immunology*
  • CD8 Antigens / immunology
  • Cell Line, Tumor
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / transplantation
  • Lymphoma, T-Cell, Peripheral / pathology
  • Lymphoma, T-Cell, Peripheral / therapy*
  • Mice
  • Molecular Targeted Therapy*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / therapy*
  • Recombinant Fusion Proteins / immunology*
  • Salvage Therapy
  • Single-Chain Antibodies / genetics
  • Single-Chain Antibodies / immunology
  • Transduction, Genetic
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology
  • Xenograft Model Antitumor Assays

Substances

  • 4-1BB Ligand
  • Antigens, Neoplasm
  • CD28 Antigens
  • CD3 Complex
  • CD3 antigen, zeta chain
  • CD5 Antigens
  • CD8 Antigens
  • Recombinant Fusion Proteins
  • Single-Chain Antibodies
  • TNFRSF9 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 9