ImmTACs overcome cytotoxic T cell suppression.

Introduction: Synthetic T cell receptor (TCR) engagers are cancer therapeutics that activate T cells through recognition of antigens on the tumor cell surface. Immune-mobilizing monoclonal TCRs against cancer (ImmTAC) are composed of the extracellular domains of the alpha and beta chains of an affinity-enhanced TCR recognizing a tumor-associated antigenic peptide-major histocompatibility complex (MHC) complex linked to an scFv fragment of an antibody against CD3ε. A first-in-class ImmTAC, Tebentafusp, is approved for the treatment of metastatic uveal melanoma. Here we asked how ImmTACs activate human primary cytotoxic T lymphocytes (CTL) in response to antigen-presenting tumor target cells. Materials and methods: We used a recently established experimental strategy to generate active and matched suppressed CTL Results: ImmTACs could elicit tumor cell cytolysis in response to endogenous antigen presentation by both active and suppressed CTL, but much less so for IFNγ secretion, in a manner dependent on the engager affinity for CD3ε. ImmTACs did so by enhancing the efficient execution of subcellular CTL polarization steps required for effective cytolysis and could trigger calcium signaling. Conclusion: These data establish that ImmTACs are powerful inducers of CTL cytotoxicity and do so with a comparable efficacy and mechanism as direct engagement of a TCR by peptide-MHC. ImmTACs retain this capability under suppressive conditions comparable to those in the tumor microenvironment.