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DNA fusion vaccine designs to induce tumor‐lytic CD8+ T‐cell attack via the immunodominant cysteine‐containing epitope of NY‐ESO 1
Author(s) -
CamposPerez Juan,
Rice Jason,
Escors David,
Collins Mary,
Paterson Alex,
Savelyeva Natalia,
Stevenson Freda K.
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28156
Subject(s) - dna vaccination , immunogenicity , epitope , lytic cycle , biology , cd8 , peptide , cytotoxic t cell , peptide vaccine , microbiology and biotechnology , virology , antigen , immunology , biochemistry , in vitro , immunization , virus
The cancer/testis antigen NY‐ESO‐1 contains an immunodominant HLA‐A2‐binding peptide (SLLMWITQC), designated S9C, an attractive target for vaccination against several human cancers. As cysteine contains a reactive SH, the oxidation status of exogenous synthetic peptide is uncertain. We have designed tolerance‐breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to tumor‐derived peptide sequences (p.DOM‐peptide), placed at the C‐terminus for optimal immunogenicity. In a “humanized” HLA‐A2 preclinical model, p.DOM‐S9C primed S9C‐specific CD8+ T cells more effectively than adjuvanted synthetic peptide. A DNA vaccine encoding the full NY‐ESO‐1 sequence alone induced only weak S9C‐specific responses, amplified by addition of DOM sequence. The analog peptide (SLLMWITQ L ) also primed peptide‐specific CD8+ T cells, again increased by DNA delivery. Importantly, T cells induced by S9C‐encoding DNA vaccines killed tumor cells expressing endogenous NY‐ESO‐1. Only a fraction of T cells induced by the S9L‐encoding DNA vaccines was able to recognize S9C and kill tumor cells. These data indicate that DNA vaccines mimic posttranslational modifications of SH‐containing peptides expressed by tumor cells. Instability of synthetic peptides and the potential dangers of analog peptides contrast with the ability of DNA vaccines to induce high levels of tumor‐lytic peptide‐specific CD8+ T cells. These findings encourage clinical exploration of this vaccine strategy to target NY‐ESO‐1.