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

Abstract

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.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Patients treated with a CEA-specific TCR experienced tumor regression accompanied with severe colitis [22] while the use of MAGE-A3 specific-TCR led to coma, leukoencephalopathy and lethal cardiac toxicity [23,24]. Thus, strategies should be elaborated to help determining the potential crossreactivities displayed by TCRs [25,26]. In sharp contrast, when targeting the cancer testis antigen NY-ESO1 using derivatives of the 1G4 TCR, impressive results (the best to date for TCR-gene transfer treatments) were obtained with objective responses ranging between 50 and 90%: two studies show the successful treatment of synovial cell sarcoma, melanoma and multiple myeloma with no immune-related adverse effects reported [27,28].…”

Tumor neoantigens: building a framework for personalized cancer immunotherapy

“…Because TAAs are normal proteins, their antigenicity depends on abnormal expression levels or context to circumvent naturally occurring mechanisms of immunological tolerance (29,30). Along these lines, TAAs usually have lower T cell receptor (TCR) affinity compared with TSAs or foreign antigens (31). The third category comprises CTAs, which are normally expressed in testis, fetal ovaries, and trophoblasts, but can also be expressed in cancer cells (17).…”

Improved structural method for T-cell cross-reactivity prediction

“…Our method can be applied in rational vaccines construction, allowing to predict the impact of heterologous immunity and anticipate individual response to vaccination (Wlodarczyk et al, 2009;Zhang et al, 2015). It can also be used to predict unexpected off-target toxicity in T cell based immunotherapies for cancer, field in which cross-reactivity has become a major concern (Linette, 2013;Stone et al, 2015).…”