Mccann, Katy J., Mander, Ann, Cazaly, Angelica, Chudley, Lindsey, Stasakova, Jana, Thirdborough, Stephen M., King, Andrew, Lloyd-Evans, Paul, Buxton, Emily, Edwards, Ceri, Halford, Sarah, Bateman, Andrew, O'Callaghan, Ann, Clive, Sally, Anthoney, Alan, Jodrell, Duncan I., Weinschenk, Toni, Simon, Petra, Sahin, Ugur, Thomas, Gareth J., Stevenson, Freda K. and Ottensmeier, Christian H. (2016) Targeting carcinoembryonic antigen with DNA vaccination: on-target adverse events link with immunological and clinical outcomes. Clinical Cancer Research, 1-33. (doi:10.1158/1078-0432.CCR-15-2507). (PMID:27091407)
Abstract
PURPOSE: We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201 binding peptide CAP-1 from carcinoembryonic antigen (CEA605-613) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin Experimental Design: Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (Arm-I) and 12 patients without radiological evidence of disease (Arm-II). Six intramuscular vaccinations of naked DNA (1mg/dose) were administered up to week 12. Clinical and immunological follow-up was to week 64 or clinical/radiological disease.
RESULTS: DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared to 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8+ T-cells, respectively. CAP-1-specific T-cells were only detectable in the blood post-vaccination, but could also be identified in previously resected cancer tissue. The gastrointestinal adverse event diarrhea was reported by 48% of patients and linked to more frequent decreases in CEA (p<0.001) and improved global immunological responses (anti-DOM responses of greater magnitude (p<0.001), frequency (p=0.004) and duration) compared to patients without diarrhea. In advanced disease patients, decreases in CEA were associated with better overall survival (HR=0.14, p=0.017). CAP-1 peptide was detectable on MHC class I of normal bowel mucosa and primary colorectal cancer tissue by mass-spectrometry, offering a mechanistic explanation for diarrhea through CD8+ T-cell attack.
CONCLUSIONS: Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody.
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