1Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 2Department I of Internal Medicine; University Hospital Cologne and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
Adoptive therapy with TCR-engineered T cells constitutes an effective treatment approach for patients with malignant disease, but is currently challenged by incomplete responses. Lack of intra-tumoral co-stimulation may contribute to immune evasion of tumors, and consequently lead to short-term responses and recurrences of tumors, a process often accompanied by low numbers and reduced activity of tumor-infiltrating T cells (Straetemans T, Mol Ther, 2015).
Here we tested the therapeutic value of TCRs that are equipped with the intracellular domain of either the co-stimulatory receptors CD28, CD40L, OX40 or ICOS, preceded by the transmembrane domain of CD28 (in extension to earlier work: Govers C, J Immunol, 2014). These co-stimulatory TCRs were gene transfered into murine T cells and subsequently tested for their impact on in vitro and in vivo T cell function in comparison to wt TCR. These new TCRs demonstrated enhanced cell surface expression and pMHC binding, except for TCR:CD40L which showed only negligible expression. Remarkably, functional T cell avidity was generally decreased compared to wt TCR, a finding which did not limit the in vivo potential of these TCRs. In fact, adoptive transfer of T cells equipped with co-stimulatory TCRs into immune competent, melanoma-bearing mice (tumor sizes > 400mm3) resulted in prolonged anti-tumor responses and survival. Notably, almost all mice treated with TCR:ICOS T cells became tumor-free and more than 50% of the mice were still cured at the end of experiment (day 80 following start of therapy; compared to about 15% cure in other TCR groups). We observed that numbers of TCR, CD4-positive T cells in blood significantly correlated to delayed tumor recurrence, and that TCR:ICOS in particular resulted in high numbers of intra-tumoral T cells, and decreased expression of co-inhibitory receptors on these T cells.
In conclusion, T cells equipped with ICOS-containing TCRs significantly improved long-term clearance of tumors, arguing for further translational studies into the therapeutic potential of this TCR.
Credits: None available.
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