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Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor.
- Source :
-
Leukemia [Leukemia] 2017 Oct; Vol. 31 (10), pp. 2151-2160. Date of Electronic Publication: 2017 Jan 12. - Publication Year :
- 2017
-
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.
- Subjects :
- 4-1BB Ligand genetics
4-1BB Ligand immunology
Animals
CD28 Antigens immunology
CD3 Complex genetics
CD3 Complex immunology
CD8 Antigens immunology
Cell Line, Tumor
Coculture Techniques
Cytotoxicity, Immunologic
Humans
Killer Cells, Natural transplantation
Lymphoma, T-Cell, Peripheral pathology
Mice
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
Salvage Therapy
Single-Chain Antibodies genetics
Single-Chain Antibodies immunology
Transduction, Genetic
Tumor Necrosis Factor Receptor Superfamily, Member 9 immunology
Xenograft Model Antitumor Assays
Antigens, Neoplasm immunology
CD5 Antigens immunology
Immunotherapy, Adoptive methods
Killer Cells, Natural immunology
Lymphoma, T-Cell, Peripheral therapy
Molecular Targeted Therapy
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy
Recombinant Fusion Proteins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 31
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 28074066
- Full Text :
- https://doi.org/10.1038/leu.2017.8