TCR affinity for p/MHC formed by tumor antigens that are self-proteins: impact on efficacy and toxicity

JD Stone, DT Harris, DM Kranz - Current opinion in immunology, 2015 - Elsevier
JD Stone, DT Harris, DM Kranz
Current opinion in immunology, 2015Elsevier
Highlights•Engineered TCRs can overcome a 'hole in the T cell repertoire'.•Affinity tuning
can yield optimal TCR candidates for adoptive T cell therapy.•On-target/off-tumor toxicity can
be revealed by more potent T cells.•Higher affinity TCRs can result in off-target reactivity with
related peptides.•Pre-clinical screening methods for off-target T cell activity are
critical.Recent studies have shown that the range of affinities of T cell receptors (TCRs)
against non-mutated cancer peptide/class I complexes are lower than TCR affinities for …
Highlights
  • Engineered TCRs can overcome a ‘hole in the T cell repertoire’.
  • Affinity tuning can yield optimal TCR candidates for adoptive T cell therapy.
  • On-target/off-tumor toxicity can be revealed by more potent T cells.
  • Higher affinity TCRs can result in off-target reactivity with related peptides.
  • Pre-clinical screening methods for off-target T cell activity are critical.
Recent studies have shown that the range of affinities of T cell receptors (TCRs) against non-mutated cancer peptide/class I complexes are lower than TCR affinities for foreign antigens. Raising the affinity of TCRs for optimal activity of CD8 T cells, and for recruitment of CD4 T cell activity against a class I antigen, provides opportunities for more robust adoptive T cell therapies. However, TCRs with enhanced affinities also risk increased reactivity with structurally related self-peptides, and off-target toxicities. Careful selection of tumor peptide antigens, in silico proteome screens, and in vitro peptide specificity assays will be important in the development of the most effective, safe TCR-based adoptive therapies.
Elsevier