Telomerase Specific Adaptive Immunotherapy 21 Rationale

Telomerase-specific adaptive immunotherapy aims to stimulate a CD8+ cytotoxic T lymphocyte (CTL) response against hTERT overexpression in cancer cells. Clinical approaches to induce CTL responses against tumor "neoantigens" generally make use of the professional antigen-presenting function of dendritic cells (DC) pulsed with neoantigen mRNA or, in the case of peptide vaccination approaches, with synthetic peptides capable of binding MHC class I molecules (HLA-A, HLA-B, or HLA-C). Pulsed DC prime CTL to lyse target cells displaying endogenously synthesized antigenic peptides in the context of the class I presentation pathway which is present in all nucleated cells (Rock and Goldberg 1999). Although antigen-specific CTL responses can be raised by these methods, clinical efficacy is limited, and the importance of both inhibiting CTL suppressive signals and inducing antigen-specific CD4+ T-helper cell support is now widely recognized (Emens 2006). T helper cells secrete cytokines that both enhance CTL activity and induce humoral and innate immunity. However, CD4+ responses are mainly raised through the endocytic class II presentation pathway, and endogenous proteins are not normally displayed in this context unless routed to the lysosomal compartment (Chamuleau et al. 2006, Humphreys et al. 2004). Immunotherapy directed against cancer-associated neoantigens is a promising approach under intense investigation (Berzofsky et al. 2004). Unfortunately, most tumor-associated antigens are represented only in small subsets of tumors and are not broad-spectrum markers. In contrast, the overexpression of telomerase in most tumor cells provides a rationale for its investigation as a potential antigen. Telomerase-specific immunotherapy represents a direct cell-killing approach not subject to the phenotypic lag.

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