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Optimizing T-cell receptor gene therapy for hematologic malignancies

Emma C. Morris and Hans J. Stauss

Article Figures & Data

Figures

  • Figure 1

    Peptide processing, HLA binding, and TCR recognition. The proteasome degrades proteins to produce peptide fragments, which are transported from the cytosol into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP) complex. Inside the ER, peptides bind to HLA class I molecules, which are then transported to the cell surface where the HLA/peptide structure is recognized by TCRs. The peptide residues important for HLA binding are indicated in pink and yellow, and the mutated residue is indicated by a cross. Note that the proteasome may not cleave at the appropriate position and that the mutation-containing peptide may not be transported by TAP or fail to bind to HLA.

  • Figure 2

    Interaction of tumor-reactive T cells with normal tissues. Cells in normal tissues may be able to provide costimulation, which results in T-cell activation and expansion (right). The interaction with cells that do not provide costimulation might induce a state of “sleepy” T-cell anergy (left).

  • Figure 3

    Risk of cross-reactivity by affinity-matured TCR. Engineered TCRs with artificially high affinity require high peptide concentration to stimulate T-cell responses (black titration curve indicates stimulation with cognate peptide). This is because of the long half-life of binding, which prevents sequential engagement of several TCRs with a single HLA/peptide ligand. Cross-reactive peptides are expected bind the same TCR with reduced affinity and binding half-life and may fall into the optimal range for sequential TCR engagement that is required for T-cell activation at low peptide concentration. Hence, the red titration curve indicates that the affinity-matured TCR is triggered by a lower concentration of cross-reactive peptide compared with cognate peptide (black curve).

  • Figure 4

    Adding and deleting genes to enhance T-cell function. Retro- and lentiviral gene transfer can be used to redirect the specificity of T cells and the metabolic functions, response to chemokines, and cytokine secretion. Gene disruption technologies can be used to delete endogenous TCR genes, HLA genes, and genes involved in negative T-cell regulation. The indicated genes are simply examples, and the editing technologies can be applied to add or disrupt any gene involved in T-cell function.