ImmTACs overcome cytotoxic T cell suppression
Lan Huynh, Abdullah Aljohani, Amal Alsubaiti, Tressan Grant, Alexandra Chapman, Gwilym Phillips, Jonathan Chamberlain, Alice Hayward-Wills, Ute Jungwirth, Mariolina Salio, Christopher J Holland, Christoph WülfingAbstract
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 TCR 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-MHC complex linked to an scFv fragment of an antibody against CD3e. 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.
Methods
We used a recently established experimental strategy to generate active and matched suppressed CTL in vitro.
Results
ImmTACs could elicit tumor cell cytolysis in response to endogenous antigen presentation by both active and suppressed CTL, but much less so IFNg secretion, in a manner dependent on the engager affinity for CD3e. 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.