Xenogeneic therapeutic cancer vaccines as breakers of immune tolerance for clinical application: To use or not to use?

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

“…during the perinatal period). 2 Some unique TAAs are directly linked to the development of cancer (e.g., products of DNA repair or apoptosis-related genes, products of tumor suppressor genes, altered proteins encoded by mutated proto-oncogenes), and in addition they could be relatively resistant to immunoselection due to their essential role in maintaining the neoplastic state. Other unique TAAs may have no direct or indirect association with malignant transformation, resulting from the general genetic instability of cancer cells.…”

“…However, TAA-mediated specificity is imperfect, as these mutated antigens arise from normal proteins and can be also expressed in altered but non-malignant cells. 2 The vast majority of TAAs are shared with normal somatic cells. The shared TAAs are divided into 4 subgroups including cancer/testis, oncofetal, differentiation, and overexpressed antigens.…”

“…Approximately 20% of all TAAs identified so far belong to this antigenic subgroup, and such proteins, as Wilm's tumor-1, telomerase, Her2/neu, and survivin fall into this category. 2,5 TAAs (mainly shared) can also be of non-protein in origin, with some tumor-associated carbohydrates 7 and (glyco) lipids 8 implicated in antitumor immune protection. Although these non-protein TAAs are not recognized in the context of conventional Major Histocompatibility Complex (MHC)-restricted T cells, they constitute targets for other components of antitumor immune responses, including natural killer (NK) cells, NK T cells, and ɣd T cells.…”

“…Although these non-protein TAAs are not recognized in the context of conventional Major Histocompatibility Complex (MHC)-restricted T cells, they constitute targets for other components of antitumor immune responses, including natural killer (NK) cells, NK T cells, and ɣd T cells. 2 …”

“…However, small interspecific structural differences in TAAs could present advantages for the construction of cancer vaccines, as xenogeneic antigens could represent an 'altered self', with sufficient differences from self-antigens to render them immunogenic, with sufficient similarities to allow reactive T cells to maintain self-recognition. 1,2 There is evidence to suggest that xenoepitopes can bind host MHC molecules more strongly compared to epitopes derived from native homologous proteins, resulting in the formation of longer-lived xenogeneic peptide/MHC complexes. Ultimately, this leads to more potent xenoantigen-induced T cell responses that are cross-reactive with self-protein-derived TAAs.…”