Therapeutic vaccination with modified vaccinia Ankara (MVA) encoding Epstein-Barr virus (EBV) target antigens in EBV+ nasopharyngeal carcinoma (NPC)

Abstract

3052 Background: EBV-associated tumors, including NPC, express the EBV-encoded proteins EBNA1 and LMP2. NPC patients demonstrate weak but nonetheless detectable CD8+ and CD4+ T cell responses to these proteins. We have developed a novel recombinant MVA vector encoding both the EBNA1 and LMP2 proteins to stimulate both the CD8+ and the CD4+ arms of the T cell immune response (J Virol 2004;78(2):768–78). Methods: This is a phase I dose escalation trial of recombinant MVA-EBNA1-LMP2 vaccine in EBV+ NPC patients (pts) in clinical remission and more than 12 weeks after completion of curative radiotherapy. Endpoints: (1) safety and toxicity, (2) immunogenicity by changes in the frequency of functional T-cell responses to MHC class I and II-restricted epitopes within EBNA1 & LMP2 in peripheral blood as quantitated by ELIspot assays at sequential time points, (3) changes in plasma EBV DNA levels. Each pts received three intradermal vaccinations at 3-weeks intervals. Cohorts of 3–6 pts will be treated at each dose level. Dose will be escalated from 5x107 to 5x108 pfu in 5 dose levels (starting dose, +100%, +100%, +67% and +50%) until maximum tolerated dose (MTD) or an immunogenic dose reached for phase II study. Results: Nine pts completed their vaccination course with three pts in each dose level up to dose level 3. No dose limiting toxicity (DLT) was observed. Main toxicities have been injection site reactions and systemic flu like symptoms. From screening of the first two vaccine recipients, T cell responses appear to have been induced to some of the relevant MHC class I and class II epitopes within the vaccine construct. Conclusions: We have developed a unique fused immunoconstruct of MHC class I (LMP2) and class II (EBNA1) epitopes delivered by MVA. This vaccine is well tolerated and even at the low initial doses tested so far appears to reactivate CD8+ and CD4+ T cell memory responses in EBV+ NPC patients. Determination of the immunogenic dose with minimal toxicity will lead to trials designed to demonstrate antitumor effects and prevention of recurrence following primary treatment. Acknowledgement: supported by Cancer Research UK and Hong Kong Cancer Fund. No significant financial relationships to disclose.