A Recombinant Modified Vaccinia Ankara Vaccine Encoding Epstein–Barr Virus (EBV) Target Antigens: A Phase I Trial in UK Patients with EBV-Positive Cancer

Abstract

Purpose Epstein-Barr virus (EBV) is associated with several cancers in which the tumour cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumour antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses. Experimental Design Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC), received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5×107 and 5×108 plaque forming units (pfu). Blood samples were taken at screening, after each vaccine cycle and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations. Results Vaccination was generally well-tolerated. Immunity increased after vaccination to at least one antigen in 8/14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments respectively. Conclusions MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South East Asia where NPC is most common. The highest dose (5×108 pfu) is recommended for investigation in current phase IB and II trials.

Therapeutic cancer vaccines

“…EBV-induced nasopharyngeal carcinoma (NPC) or other EBVinduced malignancies (65)(66)(67) showed that the vaccine was well tolerated and elicited antigen-specific T cell responses. An EBV vaccine could potentially prevent the development of EBVinduced malignancies, even if it does not prevent transmission of the virus (68).…”

Update on Head and Neck Cancer: Current Knowledge on Epidemiology, Risk Factors, Molecular Features and Novel Therapies

“…MVA-infected dendritic cells selectively reactivated LMP2-specific CD8+ memory T-cell responses as well as CD4+ memory T cells from immune donors in vitro [56]. A phase I clinical trial tested this strategy in patients who were in remission after standard therapy and showed that the MVA-based vaccine was safe and immunogenic [57]. …”

Immunotherapy against cancer-related viruses

“…The vaccine induced CD4+ and CD8+ EB-VSTs in a dose-dependent manner; however, only 2/16 vaccinated patients showed clinical benefit. Determining a correlation between detectable immune reactivity and clinical benefit for this therapy will require an expanded cohort of patients [41][42].…”