Androgen Receptor AR811 Epitope Peptide

Research background

The androgen receptor is central to prostate biology and remains the principal pharmacological target in prostate cancer, which has made its own protein sequence an object of interest as a source of tumour-associated T-cell epitopes. AR811 corresponds to residues 811 to 819 of the human androgen receptor, LLLFSIIPV, within the ligand-binding domain, the same region targeted by androgen deprivation and by receptor antagonists.

Olson and McNeel identified AR811 as an HLA-A2-restricted CD8+ T-cell epitope using motif-based prediction followed by peptide-MHC binding measurement in a T2 cell assay. Peptide-specific T-cell lines were then cultured from the peripheral blood of HLA-A2-expressing patients with prostate cancer. AR811-reactive responses were detectable in a majority of the HLA-A2-positive patients examined, reported as 8 of 15, and cytotoxic clones raised against the peptide lysed androgen-receptor-expressing prostate cancer cells in an HLA-A2-restricted manner. The clones showed polyfunctional cytokine output, producing both IFN-gamma and TNF-alpha, and immunization of HLA-A2 transgenic mice supported the immunogenicity of the sequence.

A follow-up study from the same group addressed a question with direct relevance to combination treatment strategies: whether standard androgen deprivation alters the visibility of the receptor to T cells. Prostate cancer cells deprived of androgen expressed more androgen receptor and were recognized more effectively by receptor-specific T cells, with higher activation marker and Th1 cytokine expression, increased granzyme B and increased cytotoxicity relative to androgen-replete conditions. Blockade of HLA-A2 abolished IFN-gamma release, confirming the restriction element. The ligand-binding domain has since been taken into clinical study as a vaccine antigen: a multicentre phase I trial of pTVG-AR (MVI-118), a DNA vaccine encoding the domain, reported Th1-biased immune responses against it in roughly half of evaluable patients receiving androgen deprivation, with no grade 3 or 4 adverse events attributed to vaccination.

LT9746 is supplied as a sequence-defined research reagent for antigen-specific T-cell work. The immunological findings summarized above were obtained in laboratory and early-phase clinical settings and do not establish any clinical effect of the isolated peptide.

Research applications

• HLA-A2 peptide binding and surface stabilization assays, including T2 cell binding measurement
• Tetramer and multimer assembly for enumeration of androgen-receptor-specific CD8+ T cells
• IFN-gamma ELISpot and intracellular cytokine staining with PBMC from HLA-A2-positive donors
• Generation and expansion of peptide-specific cytotoxic T-cell lines and clones
• Cytotoxicity assays against androgen-receptor-expressing prostate cancer lines, with HLA-A2 blockade as specificity control
• Immunization and challenge studies in HLA-A2 transgenic mouse models
• Studies combining androgen deprivation or receptor antagonists with antigen-specific T-cell readouts
• T-cell receptor discovery and affinity characterization against an HLA-A2-restricted tumour-associated self epitope

References

1. Olson BM, McNeel DG. CD8+ T cells specific for the androgen receptor are common in patients with prostate cancer and are able to lyse prostate tumor cells. Cancer Immunology, Immunotherapy (2011) 60:781-792. doi:10.1007/s00262-011-0987-5
2. Olson BM, Gamat M, Seliski J, et al. Prostate cancer cells express more androgen receptor (AR) following androgen deprivation, improving recognition by AR-specific T cells. Cancer Immunology Research (2017) 5:1074-1085. doi:10.1158/2326-6066.CIR-16-0390
3. McNeel DG, Saraiya B, Schweizer M, et al. Multicenter phase I trial of a DNA vaccine encoding the androgen receptor ligand binding domain (pTVG-AR, MVI-118) in patients with metastatic prostate cancer. Annals of Oncology (2019) 30 Suppl 5:v343. Annals of Oncology 2019
4. The androgen receptor - a novel target for vaccines. Nature Reviews Urology (2012). doi:10.1038/nrurol.2012.220
5. Prostate cancer vaccine - androgen receptor epitopes including AR811 (LLLFSIIPV, residues 811-819). US Patent 8,962,590 B2. US 8,962,590 B2

Related MHC class I epitope peptides

For research use only. Not for use in diagnostic or therapeutic procedures, or for human or veterinary use.