Historically five categories of tumor antigens have been utilized in immunotherapy: mutated antigens (e.g., p53 or RAS), over-expressed self-antigens (e.g., HER2/neu or MUC-1), differentiation antigens (e.g., gp100, tyrosinase), cancer testis antigens (e.g., MAGE, BAGE or CAGE families, NY-ESO-1) and viral antigens (e.g., HPV16 E6 or E7, EBV) (Cheever et al., Clin Canc Res 15:5323-5337, 2009). The advantages of therapeutic cancer vaccines utilizing proteins and peptides include the simplicity of production and the relative absence of major safety and regulatory issues.
All cells that express major histocompatibility complex (MHC) class I molecules can present short peptides (9-11 mers) from tumor-associated antigens (TAA) or viruses whose chronic persistent infection is associated with the development of malignancy (e.g. human papilloma virus, hepatitis B virus, and hepatitis C virus). However, co-stimulatory signals essential for T cell stimulation and the induction of lasting potent and effective immune responses are often absent due to the lack of induction of specific T-cell help, resulting in suboptimal and short-lived CD8+ T-cell responses caused by a lack of proper T-helper cell-mediated signaling through dendritic cells (DCs) (Zom et al., Adv Immunol 114: 177-201, 2012). In addition, vaccination with restricted MHC class I binding peptides can be associated with induction of peptide-specific tolerance rather than tumor-controlling immunity (Toes et al., J Immunol 156:3911-3918, 1996; Toes et al., Proc Natl Acad Sci USA 93:7855-7860, 1996). Furthermore, the use of a limited number of peptides within any given vaccine platform may allow the development of immune escape. Recent developments in therapeutic cancer vaccine research have included the use of TAA synthetic long peptides (SLPs) (Quakkelaar and Melief, Adv Immunol 114:77-106, 2012), as well as the use of overlapping and/or multi-epitope peptide vaccines (Walter et al., Nat Med 18:1254-1261, 2012). SLPs are synthetic peptides of 20-50 amino acids that because of their length require internalization and processing by DCs. Examples of multi-epitope peptide cancer vaccine platforms under clinical investigation include those using folate receptor alpha (NCT01606241), HER2/neu ((NCT01632332, NCT00266110, NCT00088985) and melanoma (NCTI00580060, NCT 00071981, NCT00471471, NCT00705640, NCTI00085137) peptides.
TARP (T-cell receptor γ alternate reading frame protein) is a 58 amino acid protein identified using the expressed sequence database (Maeda et al., J Biol Chem. 279:24561-24568, 2004). The mRNA is initiated in the Jγ 1 exon of the TCR γ and the protein expressed is initiated in an alternative reading frame distinct from that of the TCR γ coding sequence. Prior studies have shown that TARP is highly expressed in primary as well as metastatic prostate cancer; is expressed in prostate cancers with a range of Gleason patterns: and is expressed in both hormone sensitive and castrate resistant prostate cancer.
USPTO Backgrounds
USPTO Backgrounds