Journal
CLINICAL CANCER RESEARCH
Volume 22, Issue 19, Pages 4827-4836Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-15-2507
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Funding
- Cancer Research UK
- NIHR Experimental Cancer Medicine Centre, Southampton
- Southampton Welcome Trust Clinical Research Facility
- Cancer Research UK [22795, 18158, 15678, 18161, 15951] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [18892] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20613] Funding Source: researchfish
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Purpose: We have clinically evaluated a DNA fusion vaccine to target the HLA-A(+) 0201-binding peptide CAP-1 from carcinoembryonic antigen (CEA(605-613)) 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 nakedDNA (1 mg/dose) were administered up to week 12. Clinical and immunologic follow-up was up to week 64 or clinical/radiological disease. Results: DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared with 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 postvaccination 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 immunologic responses [anti-DOM responses of greater magnitude (P<0.001), frequency (P = 0.004), and duration] compared with 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. (C) 2016 AACR.
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