Ad5 immunity after multiple safe, homologous immunizations against tumor-associated antigens with new recombinant Ad5 vector.
85 Background: The major limitation for the use of Ad5 and other vectored vaccines is the inability to be effective in the presence of pre-existing or concomitant vector immunity. An Ad5-based vector with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), by virtue of diminished late phase viral protein expression, avoids immunological clearance and induces immune responses. METHODS: The Ad5 [E1-, E2b-] platform encoding tumor associated antigen(s) (TAA) such as a modified carcinoembryonic antigen (CEA(6D)), HER2 and HPV E6/E7, were evaluated for the induction of TAA specific immune responses and anti-tumor effects in murine models. In a phase I/II clinical trial, cohorts of patients (n=25 total) with advanced colorectal cancer, refractory to prior therapies, received escalating doses of Ad5 [E1-, E2b-]-CEA(6D) (10(9) to 10(11) vp) subcutaneously every 3 weeks for 3 immunizations. CEA-specific cell mediated immunity was measured by ELISPOT. RESULTS: In murine immunotherapy studies, mice implanted with tumors expressing TAA and subsequently treated with the Ad5 [E1-, E2b-] platform expressing that TAA had significant inhibition of tumor progression. Pre-vaccination against the TAA utilizing the Ad5 [E1-, E2b-]-TAA resulted in inhibition of tumor establishment. In a clinical trial, 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. CONCLUSIONS: The results demonstrate that the novel Ad5 [E1-, E2b-] gene delivery platform can both break tolerance and generate significant CMI responses to the TAA CEA in the setting of both naturally acquired Ad5-specific immunity and/or immunization-induced Ad5 immunity.
Morse, M; Hobeika, A; Xu, Y; Balint, J; Balcaitis, S; Lyerly, HK; Jones, FR
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