Inducible secretion of IL-21 augments anti-tumor activity of piggyBac-manufactured chimeric antigen receptor T cells
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
32950390
DOI
10.1016/j.jcyt.2020.08.005
PII: S1465-3249(20)30821-5
Knihovny.cz E-resources
- Keywords
- CAR T cells, chronic lymphocytic leukemia, interleukin 21, piggyBac transposon,
- MeSH
- Phenotype MeSH
- Immunosuppression Therapy MeSH
- Interleukin-21 MeSH
- Interleukins metabolism MeSH
- Humans MeSH
- Mice MeSH
- Neoplasms immunology therapy MeSH
- Cell Proliferation MeSH
- Receptors, Antigen, T-Cell metabolism MeSH
- T-Lymphocytes immunology MeSH
- DNA Transposable Elements genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CD19-specific chimeric antigen receptor MeSH Browser
- Interleukin-21 MeSH
- Interleukins MeSH
- Receptors, Antigen, T-Cell MeSH
- DNA Transposable Elements MeSH
BACKGROUND: The efficiency of chimeric antigen receptor (CAR) T-cell-based therapies depends on a sufficient expansion of CAR T cells in vivo and can be weakened by intra-tumoral suppression of CAR T cell functions, leading to a failure of therapy. For example, certain B-cell malignancies such as chronic lymphocytic leukemia are weakly sensitive to treatment with CAR T cells. Co-expression of proinflamatory cytokines such as IL-12 and IL-18 by CAR T cells have been shown to enhance their antitumor function. We similarly engineered CAR T cell to co-express IL-21 and studied the effects of IL-21 on CAR T cells specific to CD19 and prostate-specific membrane antigens using an in vitro co-culture model and NSG mice transplanted with B-cell tumors. RESULTS: IL-21 enhanced the expansion of CAR T cells after antigenic stimulation, reduced the level of apoptosis of CAR T cells during co-culture with tumor cells and prevented differentiation of CAR T cells toward late memory phenotypes. In addition, induced secretion of IL-21 by CAR T cells promoted tumor infiltration by CD19-specific CAR (CAR19) T cells in NSG mice, resulting in reduced tumor growth. By co-culturing CAR19 T cells with bone-marrow fragments infiltrated with CLL cells we demonstrate that IL-21 reduces the immunosupressive activity of CLL cells against CAR19 T cells. CONCLUSIONS: CAR19 T cells armed with IL-21 exhibited enhanced antitumor functions. IL-21 promoted their proliferation and cytotoxicity against chronic lymphocytic leukemia (CLL). The results suggest that arming CAR T cells with IL-21 could boost the effectiveness of CAR T-mediated therapies.
References provided by Crossref.org
