Clinical TCR gene therapy of melanoma represents a feasible and promising treatment rationale yet is currently challenged by objective response rates that stay behind those observed with conventional adoptive T cell therapy. Here, the phenotype and function of TCR-transduced T cells, considered to determine the efficacy of TCR gene therapy, were studied in relation to T cell activation and cytokine treatments. We observed that the lectin Concanavalin A (ConA), and to a lesser extent anti-CD3 and CD28 mAbs (soluble CD3/CD28), resulted in functional surface expression of the TCRαβ transgenes and enhanced fractions of CD62Lhi, CD44lonaive T cells. T cell functions and limited T cell differentiation were most significant when T cells were treated with a combination of IL-15 and IL-21 rather than IL-2. In comparison, anti-CD3 and CD28 mAbs coated to either latex or polystyrene beads (polystyrene or latex CD3/CD28) resulted in improved TCR expression levels and enhanced T cell differentiation irrespective of cytokine treatment, with effects most pronounced for polystyrene CD3/CD28. T cells demonstrated enhanced cytotoxic activity and IFNγ production when activated with CD3/CD28 beads and treated with IL-15 and IL-21, but at the same time displayed non-specific T cell responses. In contrast, ConA and soluble CD3/CD28 activations resulted in antigen-specific T cell responses. In short, we show that retroviral TCR engineering of primary T cells benefits from activation with ConA or soluble CD3/CD28 rather than immobilized anti-CD3 and CD28 mAbs with respect to T cell differentiation and antigen-specificity of T cell responses.

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Molecular Immunology
Erasmus MC: University Medical Center Rotterdam

Pouw, N.M.C, Treffers-Westerlaken, E, Mondino, A, Lamers, C.H.J, & Debets, J.E.M.A. (2010). TCR gene-engineered T cell: Limited T cell activation and combined use of IL-15 and IL-21 ensure minimal differentiation and maximal antigen-specificity. Molecular Immunology, 47(7-8), 1411–1420. doi:10.1016/j.molimm.2010.02.022