Abstract
The use of T cells reactive with intracellular tumor-associated or tumor-specific antigens has been a promising strategy for cancer immunotherapies in the past three decades, but the approach has been constrained by a limited understanding of the T cell receptor’s (TCR) complex functions and specificities. Newer TCR and T cell-based approaches are in development, including engineered adoptive T cells with enhanced TCR affinities, TCR mimic antibodies, and T cell-redirecting bispecific agents. These new therapeutic modalities are exciting opportunities by which TCR recognition can be further exploited for therapeutic benefit. In this review we summarize the development of TCR-based therapeutic strategies and focus on balancing efficacy and potency versus specificity, and hence, possible toxicity, of these powerful therapeutic modalities.
Highlights
Harnessing potent cellular effectors, such as cytotoxic T cells, and soluble molecules of the human immune system has become a successful strategy in the treatment of cancers of a variety of types
The TCR’s unique and valuable recognition properties have been taken advantage of in adoptive cell therapies, where reactive T cells are enriched or T cells are modified to express reactive TCRs, and in non-cellular therapies, which bypass the extensive process of T cell enrichment, modification and expansion, while mimicking the peptide recognition properties of the TCR in the form of soluble TCRs or antibodies
In distinct contrast to traditional antibodies and chimeric antigen receptor (CAR) T cells, TCR-based therapies recognize a short peptide bound to an major histocompatibility complexes (MHC) found on the surface of cells [144]
Summary
Harnessing potent cellular effectors, such as cytotoxic T cells, and soluble molecules of the human immune system has become a successful strategy in the treatment of cancers of a variety of types. Are identified after coculture screens with T cells by assaying for peptide dropout via DNA sequencing [175] This system has the advantages of yielding actual peptide-MHC molecules in the context of human cell surface membranes on live cells for both in vitro and in vivo work, as well as allowing functional assays such as recognition and killing of targets to be measured, but is limited in the number of peptides that can be scanned in a single assay to a few tens of thousands, whereas the proteome may contain a million potential epitope sequences that bind to an individual MHC. The MHC multimer is screened for binding with a TCR followed by sequencing of the DNA barcode to determine which peptides were able to bind the TCR of interest or to develop recognition motifs to predict additional off targets [163] Such methods may prove useful in the preclinical characterization of TCR reactivity and could be paired with tissue expression data of off-target genes to predict site-specific toxicities. A new class of bi-specific molecules, ImmTacs, are soluble T cell engagers (sTE), designed to use a TCR specific for a peptide-HLA complex, genetically linked to a single chain variable fragment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
