A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer

Graham S. Taylor, Hui Jia, Kevin Harrington, Lip Wai Lee, James E Turner, Kristin Ladell, David A. Price, Manjit Tanday, Jen Matthews, Claudia Roberts, Ceri Edwards, Lesley McGuigan, Andrew Hartley, Steve Wilson, Edwin P. Hui, Anthony T. C. Chan, Alan B. Rickinson, Neil M. Steven

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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 5x107 and 5x108 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 (5x108 pfu) is recommended for investigation in current phase IB and II trials.
Original languageEnglish
Pages (from-to)5009-5022
Number of pages14
JournalClinical Cancer Research
Volume20
Issue number19
Early online date14 Aug 2014
DOIs
Publication statusPublished - 1 Oct 2014

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Vaccinia
Human Herpesvirus 4
Vaccination
Vaccines
Antigens
Neoplasms
T-Lymphocytes
Epitopes
Immunity
Peptides
Far East
Vaccinia virus
Neoplasm Antigens
Ethnic Groups
Population
Flow Cytometry
Research Design
United Kingdom
Safety

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A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr virus (EBV) target antigens : a phase I trial in UK patients with EBV-positive cancer. / Taylor, Graham S.; Jia, Hui; Harrington, Kevin; Lee, Lip Wai; Turner, James E; Ladell, Kristin; Price, David A.; Tanday, Manjit; Matthews, Jen; Roberts, Claudia; Edwards, Ceri; McGuigan, Lesley; Hartley, Andrew; Wilson, Steve; Hui, Edwin P.; Chan, Anthony T. C.; Rickinson, Alan B.; Steven, Neil M.

In: Clinical Cancer Research, Vol. 20, No. 19, 01.10.2014, p. 5009-5022.

Research output: Contribution to journalArticle

Taylor, GS, Jia, H, Harrington, K, Lee, LW, Turner, JE, Ladell, K, Price, DA, Tanday, M, Matthews, J, Roberts, C, Edwards, C, McGuigan, L, Hartley, A, Wilson, S, Hui, EP, Chan, ATC, Rickinson, AB & Steven, NM 2014, 'A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer', Clinical Cancer Research, vol. 20, no. 19, pp. 5009-5022. https://doi.org/10.1158/1078-0432.CCR-14-1122-T
Taylor, Graham S. ; Jia, Hui ; Harrington, Kevin ; Lee, Lip Wai ; Turner, James E ; Ladell, Kristin ; Price, David A. ; Tanday, Manjit ; Matthews, Jen ; Roberts, Claudia ; Edwards, Ceri ; McGuigan, Lesley ; Hartley, Andrew ; Wilson, Steve ; Hui, Edwin P. ; Chan, Anthony T. C. ; Rickinson, Alan B. ; Steven, Neil M. / A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr virus (EBV) target antigens : a phase I trial in UK patients with EBV-positive cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 19. pp. 5009-5022.
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title = "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 5x107 and 5x108 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 (5x108 pfu) is recommended for investigation in current phase IB and II trials.",
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T1 - A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr virus (EBV) target antigens

T2 - a phase I trial in UK patients with EBV-positive cancer

AU - Taylor, Graham S.

AU - Jia, Hui

AU - Harrington, Kevin

AU - Lee, Lip Wai

AU - Turner, James E

AU - Ladell, Kristin

AU - Price, David A.

AU - Tanday, Manjit

AU - Matthews, Jen

AU - Roberts, Claudia

AU - Edwards, Ceri

AU - McGuigan, Lesley

AU - Hartley, Andrew

AU - Wilson, Steve

AU - Hui, Edwin P.

AU - Chan, Anthony T. C.

AU - Rickinson, Alan B.

AU - Steven, Neil M.

N1 - Copyright © 2014, American Association for Cancer Research.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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 5x107 and 5x108 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 (5x108 pfu) is recommended for investigation in current phase IB and II trials.

AB - 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 5x107 and 5x108 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 (5x108 pfu) is recommended for investigation in current phase IB and II trials.

U2 - 10.1158/1078-0432.CCR-14-1122-T

DO - 10.1158/1078-0432.CCR-14-1122-T

M3 - Article

C2 - 25124688

VL - 20

SP - 5009

EP - 5022

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 19

ER -