Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication.
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 CD3zeta 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.
Zhong
Xiao-Song
XS
Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Matsushita
Maiko
M
Plotkin
Jason
J
Riviere
Isabelle
I
Sadelain
Michel
M
D000818:Animals; D000954:Antigens, Surface / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D043425:Glutamate Carboxypeptidase II / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
D000954:Antigens, Surface; D018106:CD28 Antigens; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D051020:bcl-X Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II