Kurzfassung

Adoptive cellular immunotherapy (ACT) using redirected T cells has emerged as a powerful approach to successfully combat chemorefractory acute leukemia. However, its therapeutic efficacy in solid cancer is often hampered by nondurable antitumor immunity presumably caused by insufficient trafficking, homing and persistence of T cells in an immunosuppressive tumor microenvironment. Interleukin (IL)-15 has been demonstrated to play a pivotal role not only in T-cell but also NK-cell mediated...Adoptive cellular immunotherapy (ACT) using redirected T cells has emerged as a powerful approach to successfully combat chemorefractory acute leukemia. However, its therapeutic efficacy in solid cancer is often hampered by nondurable antitumor immunity presumably caused by insufficient trafficking, homing and persistence of T cells in an immunosuppressive tumor microenvironment. Interleukin (IL)-15 has been demonstrated to play a pivotal role not only in T-cell but also NK-cell mediated immunity and might therefore represent a very promising candidate in improving antitumor responses under these conditions. We therefore explored a novel targeted IL-15 superagonist composed of a soluble single-chain (sc) T-cell-receptor (TCR) identified in our department and found to recognize the melanocyte differentiation antigen tyrosine-related protein 2 (TRP-2), frequently expressed as an intact cell surface molecule in melanomas in a HLA-independent fashion. This scTCR was linked to a IL15/IL15Rα (ILR) complex and additionally fused with the human IgG1-Fc domain to prolong bioactivity. Recombinant TRP2-TCR-ILR fusionprotein was produced using the Expi293 system™ to be affinity purified and initially characterized by western blotting. First in vitro analyses revealed that T cell mediated immune responses can be clearly enhanced by addition of the TRP-2-ILR superagonist, and in vivo studies using a NSG xenograft model as well as an immunocompetent C57BL/6 melanoma model to evaluate improvement of immune responses to melanoma after adoptive transfer of either non-directed or TRP-2 reprogrammed human or murine T-cells or NK-cells and combinations thereof are in progress. The working hypothesis is that upon binding of the TCR to its antigen on melanoma cells signaling through the IL15R will promote T cell activation and induce cytolytic activity as recently shown for a HLA2-restricted p53-specific TCR linked to IL-2. Moreover, NK-cells will be recruited to the tumor site and support antitumor immunity. Finally, targeting IL-15 to tumor cells might help to reduce nonspecific off-target activity often observed with cytokines used to boost immunity.
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