Figure 1.
Comparison of approved T cell therapies. Shown from left to right are the principles by which T cell therapies take advantage of the TCR: by leveraging natural T cells, which through their TCR recognize a tumor-associated antigen peptide/MHC complex (pMHC); by employing T cells with a transgenic TCR recognizing a defined pMHC target; by utilizing genetically engineered T cells expressing a recombinant CAR; and by engaging T cells whereby the TCR is connected via a TCE to a surface antigen or pMHC on target cells. Therapeutics are listed below each modality with asterisks denoting FDA-approved drugs. Each T cell naturally expresses only one TCR specific for a peptide presented by MHC molecules on the surface of target cells. Recognition is through heterodimeric α/β chains of the TCR, each of which comprises an antigen-binding variable (V) domain followed by a constant (C) domain, a transmembrane (TM) domain, and a short cytoplasmic domain. TM and cytoplasmic domains associate with intracellular, signal-transducing TCRζ subunits and CD3εδ and εγ heterodimeric subunits. TCR-T cells harbor engineered TCRs whereby defined α and β chain V regions are selected to bind predefined pMHC molecules, such as MAGE-A4 peptide in the case of Tecelra (Keam, 2024). CAR-T cells employ antibody-derived domains to recognize surface antigens such as CD19 or BCMA on target cells. The antibody fragments are fused to a TM and signal-transducing domains derived from costimulatory CD28 or CD137 receptors, and only use TCRζ for T cell activation. TCEs are soluble antibody-based constructs that are bispecific for an antigen on target cells and the CD3ε subunit shared by all TCRs. TCEs using TCR fragments or TCR-mimetic antibodies are bispecific for CD3ε on T cells and a defined pMHC on target cells. An example is tebentafusp whose TCR moiety binds gp100 peptide/HLA-A*02:01 MHCs on melanoma cells (Liddy et al., 2012; Lowe et al., 2019).

Comparison of approved T cell therapies. Shown from left to right are the principles by which T cell therapies take advantage of the TCR: by leveraging natural T cells, which through their TCR recognize a tumor-associated antigen peptide/MHC complex (pMHC); by employing T cells with a transgenic TCR recognizing a defined pMHC target; by utilizing genetically engineered T cells expressing a recombinant CAR; and by engaging T cells whereby the TCR is connected via a TCE to a surface antigen or pMHC on target cells. Therapeutics are listed below each modality with asterisks denoting FDA-approved drugs. Each T cell naturally expresses only one TCR specific for a peptide presented by MHC molecules on the surface of target cells. Recognition is through heterodimeric α/β chains of the TCR, each of which comprises an antigen-binding variable (V) domain followed by a constant (C) domain, a transmembrane (TM) domain, and a short cytoplasmic domain. TM and cytoplasmic domains associate with intracellular, signal-transducing TCRζ subunits and CD3εδ and εγ heterodimeric subunits. TCR-T cells harbor engineered TCRs whereby defined α and β chain V regions are selected to bind predefined pMHC molecules, such as MAGE-A4 peptide in the case of Tecelra (Keam, 2024). CAR-T cells employ antibody-derived domains to recognize surface antigens such as CD19 or BCMA on target cells. The antibody fragments are fused to a TM and signal-transducing domains derived from costimulatory CD28 or CD137 receptors, and only use TCRζ for T cell activation. TCEs are soluble antibody-based constructs that are bispecific for an antigen on target cells and the CD3ε subunit shared by all TCRs. TCEs using TCR fragments or TCR-mimetic antibodies are bispecific for CD3ε on T cells and a defined pMHC on target cells. An example is tebentafusp whose TCR moiety binds gp100 peptide/HLA-A*02:01 MHCs on melanoma cells (Liddy et al., 2012; Lowe et al., 2019).

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