Challenges and solutions for therapeutic TCR-based agents

Abstract

Recent development of methods to discover and engineer therapeutic T-cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that TCR-based agents will be similarly important contributors to the treatment of a variety of medical conditions, especially cancers. TCR engineered cells, soluble TCRs and their derivatives, TCR-mimic antibodies, and TCR-based CAR T cells promise the possibility of highly specific drugs that can expand the scope of immunologic agents to recognize intracellular targets, including mutated proteins and undruggable transcription factors, not accessible by traditional antibodies. Hurdles exist regarding discovery, specificity, pharmacokinetics, and best modality of use that will need to be overcome before the full potential of TCR-based agents is achieved. HLA restriction may limit each agent to patient subpopulations and off-target reactivities remain important barriers to widespread development and use of these new agents. In this review we discuss the unique opportunities for these new classes of drugs, describe their unique antigenic targets, compare them to traditional antibody therapeutics and CAR T cells, and review the various obstacles that must be overcome before full application of these drugs can be realized.

Keywords: CAR T cells; HLA restriction; TCR gene therapy; TCR-mimic mAb; off-target toxicity; soluble TCR.

Figure 1.. Protecting the Engineered cell.

There are two general strategies to generate stealthy, off-the-shelf allogenic donor cells for adoptive cell therapy. Methods include editing endogenous genes of TCRα/β chains, β2-microglobulin (B2M), and MHC class II transactivator (CIITA); by CRISPR mediated gene deletion or disruption of their expression by insertion of new genes such as engineered TCR can reduce recognition by the host. Alternatively, alloimmune defense receptor (ADR), “Do not eat me” CD47, Streptococcus pyogenes (IdeS), and HAL-E proteins can protect allogeneic cells from rejection by the host immune cells. See section 7 for more information. All figures were created by using BioRender.

Figure 2.. Comparison of Characteristics of TCR T-cell and CAR-T-cell formats.

(left) TCR therapy targets a large universe of intracellular tumor antigens that are presented on the cell surface as peptide fragments by MHC molecules. The recognition of the antigen occurs via alpha beta TCR/CD3 complex. (right) Most current CAR-T-cell therapies target cell surface and lineage proteins that are shared between tumor and normal cells. The recognition of the target is through the scFv of an mAb directed to the surface target protein, which was linked to the T-cell activation molecules CD28 or 41BB and CD3 zeta chain. All figures were created by using BioRender.

Figure 3.. Characteristics of new hybrid T-cell formats.

(left). Ab-TCR is a new TCR/CAR-T format, which consists of two separate activation domains: the first domain uses a Fab specific for a tumor antigen, linked to gamma/delta TCR to facilitate a natural T-cell activation. The second domain uses a scFv of an mAb targeting a second tumor antigen, linked to a costimulatory molecule, CD28, down-stream of a signaling molecule needed to for fully activate T-cells and duel targeting tumor antigens This new format of CAR-T-cells could avoid excessive synthetic activation and toxicity caused by traditional CAR-T-cells that assemble T-cell activation molecules in one construct. (right). TCRm CAR-T-cells use traditional CAR-T construct, however, they are able to target intracellular tumor antigen-derived peptide/MHC complexes, by using scFv derived from TCR mimic mAbs. CSR: Costimulatory signaling receptor. All figures were created by using BioRender.