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


METHODS
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.
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.
Katy J
KJ
McCann
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.
Ann
A
Mander
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.
Angelica
A
Cazaly
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.
Lindsey
L
Chudley
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.
Jana
J
Stasakova
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.
Stephen
S
Thirdborough
University Hospital Southampton NHS Trust, Southampton, UK.
Andrew
A
King
NHS Blood and Transplant, Clinical Biotechnology Centre, University of Bristol, Bristol, UK.
Paul
P
Lloyd-Evans
Cancer Research UK Centre for Drug Development, London, UK.
Emily
E
Buxton
Cancer Research UK Centre for Drug Development, London, UK.
Ceri
C
Edwards
Cancer Research UK Centre for Drug Development, London, UK.
Sarah
S
Halford
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.|University Hospital Southampton NHS Trust, Southampton, UK.
Andrew
A
Bateman
Portsmouth Hospitals NHS Trust, Portsmouth, UK.
Ann
A
O'Callaghan
Western General Hospital, Edinburgh, UK.
Sally
S
Clive
St. James's Institute of Oncology, Leeds, UK.
Alan
A
Anthoney
CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Duncan I
DI
Jodrell
Immatics biotechnologies, Tübingen, Germany.
Toni
T
Weinschenk
TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany.|BioNTech Cell & Gene Therapies GmbH, Mainz, Germany.
Petra
P
Simon
TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Ugur
U
Sahin
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.|University Hospital Southampton NHS Trust, Southampton, UK.
Gareth J
GJ
Thomas
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.
Freda K
FK
Stevenson
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.|University Hospital Southampton NHS Trust, Southampton, UK.
Christian H
CH
Ottensmeier
D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002277:Carcinoma / Q000188:drug therapy*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000276:immunology / Q000627:therapeutic use; D019444:Vaccines, DNA / Q000627:therapeutic use*
C405522:CAP1-6D; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D009842:Oligopeptides; D019444:Vaccines, DNA