The first stumbling block is encountered during thymic maturation.
While mature naïve virus-specific T cells are ‘non-self’-specific and are
generally positively selected in the thymus, T cells specific for tumor antigens are primarily ‘self’-specific and, therefore, are negatively selected by
thymic clonal deletion. The result is that the naïve repertoire of mature
circulating anti-cancer T cells in mice and humans is narrow, with low frequencies of specific cells and only low-to-intermediate TCR affinities.
Such low affinity and precursor frequencies imply significant limitations
for T cell priming and target cell lysis. As mentioned above, it is assumed
that this limitation may not (or to a lesser extent) apply to mutated neoantigens.