A Uk-Based Phase I Trial Of Recombinant Modified Vaccinia Ankara (Mva) Vaccine Encoding Epstein-Barr Virus (Ebv) Antigens
JOURNAL OF CLINICAL ONCOLOGY(2011)
Abstract
e13028 Background: EBV is harboured in various human cancers despite abundant T cell responses, partly through selective antigen expression in malignant cells. A recombinant virus MVA-EL, encoding two EBV tumour antigens as an EBNA1/LMP2 fusion, was designed to boost immunity in Asian populations for whom EBV+ nasopharyngeal carcinoma (NPC) is endemic. A phase I trial extended this application, testing its safety and immunogenicity in UK patients. Methods: Patients with EBV+ cancer, >12 weeks after primary therapy, received 3 intra-dermal vaccinations of MVA-EL at 3-weekly intervals, with dose escalations of 5x107, 1x108, 2x108, 3.3x108 and 5x108pfu. Blood samples were taken at screening, after each vaccine cycle and up to 12 months post-vaccination. Peripheral blood mononuclear cells (PBMC) were tested for spot-forming cells (sfc) in interferon (IFN)-gamma ELIspot assays against complete EBNA1 and LMP2 15-mer peptide mixes and against defined epitope peptides selected according to MHC-type. Results: Sixteen patients, all with NPC, participated (n=6, 3, 4, 2 and 1 in successive cohorts). One dose limiting toxicity was observed: a grade 3 injection site reaction in patient 1. The trial closed because of vaccine expiry and because combining data with a parallel trial permitted dose recommendation for phase II. Patients 15 and 16 were not evaluable for immunity. Pre-existing immunity was observed in 11/14 (EBNA1) and 10/14 (LMP2) patients. Immunity increased after vaccination in 7/14 (EBNA1) and 6/14 (LMP2) patients. In 9 patients with paired samples tested against 15-mer mixes, antigen recognition significantly increased from pre-vaccination medians of 80 sfc/106 PBMC (EBNA1) and 77 (LMP2), to post vaccination medians of 139 (EBNA1, p=0.01) and 350 (LMP2, p=0.02). Screening on defined peptides identified individuals mounting both MHC I and II-restricted responses to known epitopes in one or both target antigens. Conclusions: MVA-EL is safe and immunogenic in the UK population. A phase IB trial at 5x108pfu is needed in the UK to characterise immunity in detail at the recommended dose. Acknowledgement: supported by Cancer Research UK.
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Key words
recombinant modified vaccinia ankara,ebv,vaccine,antigens,uk-based,epstein-barr
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