Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI responses in patients with advanced CEA-expressing malignancies in a phase I/II clinical trial.

Abstract

2585 Background: Adenovirus (Ad) vectors are promising platforms for use as cancer vaccines because of their substantial immunogenicity; however, Ad-specific neutralizing antibodies, present due to natural infection, limit their use. We created a new vector containing additional deletions of the E2b gene and observed that this Ad5 [E1-, E2b-] vector, engineered to express carcinoembryonic antigen (CEA(6D)), could induce antitumor immune responses in mice despite pre-existing Ad5 immunity. The purpose of the current translational study was to evaluate the immunologic effect of increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice and then to extended these pre-clinical observations into a phase I/II study. Methods: Ad5 naïve female C57Bl/6 mice, 4-6 weeks old, were immunized subcutaneously 3 times at 2 week intervals with doses of 1.4X107 viral particles (vp) up to1.4X109 vp of Ad5 [E1-, E2b-]-CEA(6D). Two weeks after the last immunization, splenocytes were harvested for immune determinations. Cohorts of patients (n=25 total) with advanced colorectal cancer, refractory to prior therapies, received escalating doses of Ad5 [E1-, E2B-]-CEA(6D) (109 to 1011 vp) subcutaneously every 3 weeks for 3 immunizations.CEA-specific cell mediated immunity was measured by ELISPOT. Results: Increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice induced increasing CEA-specifc CMI responses. Similarly, patients who received the highest dose of Ad5 [E1-, E2b-]-CEA(6D) exhibited the highest levels of CEA-specific CMI responses. The induction of CEA-specific CMI responses increased over the course of the 3 injections despite the presence of pre-existing Ad5 immunity in the majority (75%) of patients. There were no drug related grade 3/4 toxicities.Two patients with stable disease remained so during the study. All other patients experienced progressive disease; however, 1-year survival was 54%. Conclusions: Multiple homologous doses of Ad5 [E1-, E2b-]-CEA(6D) could break tolerance and generate CEA-specific CMI responses in the setting of Ad specific immunity in colorectal cancer patients.