期刊
MOLECULAR THERAPY
卷 18, 期 2, 页码 413-420出版社
CELL PRESS
DOI: 10.1038/mt.2009.210
关键词
-
资金
- NIH [CA59350, CA23766, CA08748]
To enhance the strength of activation afforded by tumor antigen-specific receptors, we investigated the effect of adding combined CD28 and 4-1BB costimulatory signaling domains to a chimeric antigen receptor (CAR) specific for prostate-specific membrane antigen (PSMA). Having transferred receptors encompassing the CD28, 4-1BB, and/or CD3 zeta cytoplasmic domains in primary human CD8+ T cells, we find that the P28BBz receptor, which includes all three signaling domains, is superior to receptors that only include one or two of these domains in promoting cytokine release, in vivo T-cell survival and tumor elimination following intravenous T-cell administration to tumor-bearing severe combined immunodeficient (SCID)/beige mice. Upon in vitro exposure to PSMA, the P28BBZ receptor-induced the strongest PI3 Kinase/Akt activation and Bcl-X-L expression, and the least apoptosis in transduced peripheral blood CD8+ T cells. These findings further support the concept of integrating optimized costimulatory properties into recombinant antigen receptors to augment the survival and function of genetically targeted T cells within the tumor micro-environment.
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