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.