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Clin Cancer Res. 2016 Oct 1;22(19):4827-4836. doi: 10.1158/1078-0432.CCR-15-2507. Epub 2016 Apr 18.

Targeting Carcinoembryonic Antigen with DNA Vaccination: On-Target Adverse Events Link with Immunologic and Clinical Outcomes.

Author information

1
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.
2
University Hospital Southampton NHS Trust, Southampton, UK.
3
NHS Blood and Transplant, Clinical Biotechnology Centre, University of Bristol, Bristol, UK.
4
Cancer Research UK Centre for Drug Development, London, UK.
5
Portsmouth Hospitals NHS Trust, Portsmouth, UK.
6
Western General Hospital, Edinburgh, UK.
7
St. James's Institute of Oncology, Leeds, UK.
8
CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
9
Immatics biotechnologies, Tübingen, Germany.
10
TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
11
BioNTech Cell & Gene Therapies GmbH, Mainz, Germany.
#
Contributed equally

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 (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. Clin Cancer Res; 22(19); 4827-36. ©2016 AACR.

PMID:
27091407
PMCID:
PMC5330406
DOI:
10.1158/1078-0432.CCR-15-2507
[Indexed for MEDLINE]
Free PMC Article

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