Clinical and immunological responses to a DNA fusion vaccine in patients with carcinoembryonic antigen-expressing tumors: A Cancer Research UK phase I/II study.

Abstract

2579 Background: We have designed DNA fusion vaccines encoding a tumor-derived peptide, linked to a tolerance-breaking domain sequence (DOM) from tetanus toxin. One peptide sequence from prostate cancer is in clinical trial with CD8+ T-cell responses detected in 60% of patients. For patients with CEA expressing cancers, the target peptide is an HLA-A2-binding sequence, CAP-1 (CEA605–613). Methods: We undertook a single dose level, two-arm phase I/II study to examine the safety and immunogenicity of the DNA fusion vaccine (p.DOM-CAP-1) in patients with CEA-expressing cancers (bowel, lung, and breast cancer). 1mg/dose of DNA was given at weeks 0, 1, 2, 4, 8 and 12. 15 patients with measurable disease were recruited to arm I, 12 patients without radiological evidence of disease to arm II of the study. Results: Interim immunological results reveal humoral and cellular responses to the DOM vaccine component in both arms, confirming successful delivery of the vaccine. CAP1–specific CD8+ T-cells were detected using ex vivo and cultured IFNγ ELISPOT, demonstrating CAP-1 antigenicity. To date immune assessment is mainly in patients with advanced disease (15/15 arm I, 5/12 arm II). In these 20 patients 50% have developed a FrC cellular responses, 35% a CAP-1 cellular response. Follow-up is almost complete with 1 timepoint each in two patients outstanding. We observed an unexpected, high incidence of gastrointestinal adverse events (GI AE) notably diarrhoea (12/27) in vaccinated patients, not observed in the trial of prostate cancer patients. This occurred early after vaccination in patients both with and without measurable disease. In arm 1 these adverse events appear to be coincident with an increased time to clinical and radiological disease progression, longer on-study follow up, decreases in, or stable CEA levels, and longer duration of positive anti-DOM cellular responses (mean 35±14 weeks compared to 7.5± 5 weeks [p<0.006] for those without diarrhea). Conclusions: The early clinical and immunological data indicate that the vaccine is immunogenic. Immune responses correlate with GI-associated effects and an increased time to disease progression. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genvax Genvax Genvax