A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells

Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin MC3-3320, Houston, TX 77030, USA.
Molecular Therapy (Impact Factor: 6.23). 12/2005; 12(5):933-41. DOI: 10.1016/j.ymthe.2005.04.016
Source: PubMed


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.

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    • "This is essentially important since naive and antigen-experienced T cells have different functional capabilities which can make them more or less effective for adoptive cell therapy (Jameson and Masopust 2009). CAR modification can involve one or more Tcell-activating signals which will be associated with the higher potential of T cells to proliferate, persist, and lyse target cells (Pulè et al. 2005). Finally, the ability to produce a large number of tumor-specific T cells in a moderately short period of time makes this technique more attractive to use in the clinical background (Hollyman et al. 2009, June 2007). "
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    • "demonstrated long-term persistence in patients [19], and third-generation CD28-CD134 CAR T cells had enhanced in vitro expansion, survival and effector functions [20]. However, widely variable efficacy and persistence between patients is still reported in clinical trials of these later-generation receptors [21e23]. "
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