Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI 3 kinase/AKT/Bcl-X L activation and CD8 T cell-mediated tumor eradication Journal Article

   

Authors:	Zhong, X. S.; Matsushita, M.; Plotkin, J.; Riviere, I.; Sadelain, M.
Article Title:	Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI 3 kinase/AKT/Bcl-X L activation and CD8 T cell-mediated tumor eradication
Abstract:	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 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 PI 3 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 microenvironment. © The American Society of Gene & Cell Therapy.
Keywords:	signal transduction; protein kinase b; controlled study; unclassified drug; human cell; nonhuman; flow cytometry; neoplasms; cd8+ t lymphocyte; lymphocyte proliferation; t lymphocyte; cd8-positive t-lymphocytes; mouse; animals; mice; cell survival; cells, cultured; mus; apoptosis; animal experiment; animal model; gene function; in vivo study; enzyme activation; in vitro study; mice, scid; protein bcl xl; bcl-x protein; phosphatidylinositol 3 kinase; prostate cancer; cancer inhibition; membrane antigen; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; immunoblotting; immunostimulation; cytokine release; nih 3t3 cells; lymphocyte antigen receptor; cd28 antigen; antigens, cd28; glutamate carboxypeptidase ii; antigens, surface; cd137 antigen; prostate specific memebrane antigen; protein p28bbz receptor; antigens, cd137
Journal Title:	Molecular Therapy
Volume:	18
Issue:	2
ISSN:	1525-0016
Publisher:	Nature Publishing Group
Date Published:	2010-02-01
Start Page:	413
End Page:	420
Language:	English
DOI:	10.1038/mt.2009.210
PUBMED:	19773745
PROVIDER:	scopus
PMCID:	PMC2839303
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-76349087378&partnerID=40&md5=e8912de6abde88133445c8a9efbc9855
Notes:	--- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "CODEN: MTOHC" - "Source: Scopus"