Page 28 - Read Online

Tokuyasu et al. J Cancer Metastasis Treat 2018;4:2 I http://dx.doi.org/10.20517/2394-4722.2017.52 Page 9 of 24

Also, binding data does not exist for many less common MHC alleles, which has given rise to “pan MHC”
algorithms with somewhat reduced performance. Therapeutic strategies based on so-called promiscuous
epitopes that bind to several MHC alleles may place less stringent requirements on the accuracy of binding
predictions [107] .

The extent to which epitope binding scores are a good surrogate for immunogenicity remains unclear.
[29]
Peptide binding stability rather than affinity has been proposed as a better predictor of immunogenicity .
Numerous factors can affect antigen presentation and recognition processes, such as pH, inflammation, and
peptide post-translational modifications [108] .

Many of the structural aspects of peptide-MHC binding and TCR recognition are reviewed by Hudrisier
and Gairin [109] . Important aspects of the problem formulation can be found e.g. in the references cited by
[14]
Meydan et al. . A recent examination of empirical TCR-pMHC kinetic constants measured in three-
dimensional assays suggests these may not accurately reflect dynamics in a two-dimensional context, such as
T cell scanning of the APC surface [110] . This could suggest that some of the data underlying current epitope
binding prediction algorithms needs to be re-measured.

In general, while immunogenic antigens tend to have high binding scores, the converse does not hold [111] . In
addition, indels and gene fusions are typically not chosen, due to the difficulty of predicting binding. Snyder
and Chan [101] caution that current prediction tools on their own are not ready for routine clinical use.

Choice of epitope candidates
In tumors with a large number of mutations, the candidate filtering step is essential to avoid being
overwhelmed by false positives [112] . Mass spectrometry has been effectively used for this task by identifying
MHC-bound peptides [113] . Indeed, it can be used to generate candidates on its own [114,115] . There remain
possible issues with sensitivity and translation into a clinical setting [112] . Combining functional analysis and T
cell detection via multimers can help in the search for tumor rejection epitopes [116] . Proximity ligation assays
can assess whether an antigen is presented in situ, although this requires a mutant-specific antibody [117] .
Another approach tests epitopes experimentally in MHC-transgenic mice [118,119] . Further work is necessary to
validate the efficacy of such workflows [120] . An interesting suggestion is that PD-1 peripheral blood cells are
+
enriched in tumor neoantigens, from which candidate epitopes can be derived [121] .

There is a general exhortation to prioritize genes that target essential tumor “driver” functions such as growth
and survival. This however may not be too helpful, as only a small percentage of neoantigens are of this type
in e.g. melanoma [112] , the vast majority being “passenger” mutants not associated with cell transformation.
Efforts to expand and/or refine the list of functional cancer genes may help in this regard [122,123] .

Current vaccine strategy employs several epitopes to address tumor heterogeneity and reduce acquisition
of resistance, while also compensating for the imperfect predictive value of pMHC binding tools. The
phenomena of immunodominance [124-127] and T cell cross-reactivity [128] suggests that simply increasing the
number of epitopes in a vaccine may not be advisable, as a suboptimal epitope may interfere with the others
in a dominance hierarchy, and auto-immunity remains an issue. Indeed, pioneering efforts in cancer epitope
selection [113,129] found possible instances of immunodominance. Initial experience with long peptides on the
other hand suggested this may not be an issue [130] . Further work is required to understand how to choose the
number of epitopes to include in a vaccine, which could be e.g. cancer type-specific. The thinking behind
many current vaccine approaches is examined by Kumai et al. [131] who also describe four steps to developing
cancer vaccines and five ways of monitoring the response.

Initial effort e.g. in adoptive cell transfer was focused on MHC-I restricted epitopes to elicit direct tumor
cell killing. Attention has now shifted to MHC-II restricted epitopes, in part due to the fuller realization that