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Identification of Chimeric Antigen Receptors That Mediate Constitutive or Inducible Proliferation of T Cells
- Source :
- Cancer Immunology Research. 3:356-367
- Publication Year :
- 2015
- Publisher :
- American Association for Cancer Research (AACR), 2015.
-
Abstract
- This study compared second-generation chimeric antigen receptors (CAR) encoding signaling domains composed of CD28, ICOS, and 4-1BB (TNFRSF9). Here, we report that certain CARs endow T cells with the ability to undergo long-term autonomous proliferation. Transduction of primary human T cells with lentiviral vectors encoding some of the CARs resulted in sustained proliferation for up to 3 months following a single stimulation through the T-cell receptor (TCR). Sustained numeric expansion was independent of cognate antigen and did not require the addition of exogenous cytokines or feeder cells after a single stimulation of the TCR and CD28. Results from gene array and functional assays linked sustained cytokine secretion and expression of T-bet (TBX21), EOMES, and GATA-3 to the effect. Sustained expression of the endogenous IL2 locus has not been reported in primary T cells. Sustained proliferation was dependent on CAR structure and high expression, the latter of which was necessary but not sufficient. The mechanism involves constitutive signaling through NF-κB, AKT, ERK, and NFAT. The propagated CAR T cells retained a diverse TCR repertoire, and cellular transformation was not observed. The CARs with a constitutive growth phenotype displayed inferior antitumor effects and engraftment in vivo. Therefore, the design of CARs that have a nonconstitutive growth phenotype may be a strategy to improve efficacy and engraftment of CAR T cells. The identification of CARs that confer constitutive or nonconstitutive growth patterns may explain observations that CAR T cells have differential survival patterns in clinical trials. Cancer Immunol Res; 3(4); 356–67. ©2015 AACR.
- Subjects :
- Interleukin 2
Cancer Research
CD3 Complex
Recombinant Fusion Proteins
T-Lymphocytes
Genetic Vectors
Immunology
Receptors, Antigen, T-Cell
Mice, SCID
Biology
Lymphocyte Activation
Immunotherapy, Adoptive
Article
Immunophenotyping
Cytokine-Induced Killer Cells
CD28 Antigens
Antigen
Mice, Inbred NOD
medicine
Animals
Humans
Cytotoxic T cell
Cell Proliferation
Ovarian Neoplasms
Lentivirus
T-cell receptor
CD28
Xenograft Model Antitumor Assays
Chimeric antigen receptor
Cell biology
Cytokines
Interleukin-2
Female
Cytokine secretion
Chemokines
Signal transduction
human activities
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 23266074 and 23266066
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- Cancer Immunology Research
- Accession number :
- edsair.doi.dedup.....f16bfc3e4d3a93d981b4c4989621a48a