Monoclonal antibodies are at the vanguard of the most promising
cancer treatments. Whereas traditional therapeutic
antibodies have been limited to extracellular
antigens, T cell receptor mimic (TCRm)
antibodies can target intracellular
antigens presented by cell surface major histocompatibility complex (MHC)
proteins. TCRm
antibodies can therefore target a repertoire of otherwise undruggable
cancer antigens. However, the consequences of off-target
peptide/MHC recognition with engineered T cell
therapies are severe, and thus there are significant safety concerns with TCRm
antibodies. Here we explored the specificity and safety profile of a new TCRm-based T cell
therapy for
hepatocellular carcinoma (HCC), a solid
tumor for which no effective treatment exists. We targeted an
alpha-fetoprotein peptide presented by
HLA-A*02 with a highly specific TCRm, which crystallographic structural analysis showed binds directly over the HLA
protein and interfaces with the full length of the
peptide. We fused the TCRm to the γ and δ subunits of a TCR, producing a signaling AbTCR construct. This was combined with an scFv/CD28 co-stimulatory molecule targeting
glypican-3 for increased efficacy towards
tumor cells. This AbTCR + co-stimulatory T cell
therapy showed potent activity against AFP-positive
cancer cell lines in vitro and an in an in vivo model and undetectable activity against AFP-negative cells. In an in-human safety assessment, no significant adverse events or
cytokine release syndrome were observed and evidence of efficacy was seen. Remarkably, one patient with metastatic HCC achieved a complete remission after nine months and ultimately qualified for a
liver transplant.