Walseng et al. fused a soluble TCR construct to a CAR-signaling tail, resulting in the aptly named TCR-CAR. The TCR portion maintained the advantage of specifically targeting epitopes presented on MHC molecules, while the CAR signaling portion allowed for the transduction of cell types beyond just T cells. The functionality (cytokine release, degranulation, cell killing) of TCR-CARs was demonstrated in T and NK cells.
Effector T cells equipped with engineered antigen receptors specific for cancer targets have proven to be very efficient. Two methods have emerged: the Chimeric Antigen Receptors (CARs) and T-cell Receptor (TCR) redirection. Although very potent, CAR recognition is limited to membrane antigens which represent around 1% of the total proteins expressed, whereas TCRs have the advantage of targeting any peptide resulting from cellular protein degradation. However, TCRs depend on heavy signalling machinery only present in T cells which restricts the type of eligible therapeutic cells. Hence, an introduced therapeutic TCR will compete with the endogenous TCR for the signalling proteins and carries the potential risk of mixed dimer formation giving rise to a new TCR with unpredictable specificity. We have fused a soluble TCR construct to a CAR-signalling tail and named the final product TCR-CAR. We here show that, if expressed, the TCR-CAR conserved the specificity and the functionality of the original TCR. In addition, we demonstrate that TCR-CAR redirection was not restricted to T cells. Indeed, after transduction, the NK cell line NK-92 became TCR positive and reacted against pMHC target. This opens therapeutic avenues combing the killing efficiency of NK cells with the diversified target recognition of TCRs.
Author Info: (1) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. (2) Department for Cellular Therapy, Department for Cancer T
Author Info: (1) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. (2) Department for Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway. (3) Department for Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway. (4) Department for Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway. (5) Department for Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway. (6) Department for Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway. (7) Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. (8) Department for Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway. (9) Department for Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway. sebastw@rr-research.no. Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. sebastw@rr-research.no. Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway. sebastw@rr-research.no.
