A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells.
The transduction of primary T cells to express chimeric T cell receptors (cTCR) for redirected targeting of tumor cells is an attractive strategy for generating tumor-specific T cells for adoptive therapy. However, tumor cells rarely provide costimulatory signals and hence cTCRs that transmit just a CD3zeta signal can only initiate target cell killing and interferon-gamma release and fail to induce full activation. Although incorporation of a CD28 component results in IL-2 release and limited proliferation, T cell activation remains incomplete. OX40 transmits a potent and prolonged T cell activation signal and is crucial for maintaining an immunological response. We hypothesize that the CD28-OX40-CD3zeta tripartite cytoplasmic domain will provide a full complement of activation, proliferation, and survival signals for enhanced anti-tumor activity.
Pulè
Martin A
MA
Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin MC3-3320, Houston, TX 77030, USA.
Straathof
Karin C
KC
Dotti
Gianpietro
G
Heslop
Helen E
HE
Rooney
Cliona M
CM
Brenner
Malcolm K
MK
D018106:CD28 Antigens; D017252:CD3 Complex / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505716:TNFRSF4 protein, human