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Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model

Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model
Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model
PURPOSE: Neuroblastoma is one of the commonest extra-cranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models.

EXPERIMENTAL DESIGN: Neuroblastoma bearing mice were treated with mAb targeting 4-1BB, CD40 and CTLA-4 alone, or in combination with a peptide derived from the tumor antigen survivin (GWEDPPNDI). Survivin-specific immune response and therapeutic efficacy was assessed.

RESULTS: In the Neuro2a model, treatment of established tumor with either anti-4-1BB, anti-CD40 or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40-60% of mice. This is dependent on NK and CD8+ T cells and is associated with tumor CD8+ lymphocyte infiltrate. Successful therapy is achieved only if mAb is given to mice once tumors are established, suggesting dependence on sufficient tumor to provide antigen. In the more aggressive AgN2a and NXS2 models, single agent mAb therapy provides ineffective therapy. However if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination then 60% long term survival is achieved. This is associated with the generation of survivin-specific T cell immunity, which again is only demonstrated in the presence of tumor antigen.

CONCLUSIONS: These data suggest the combination of antigen and co-stimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal-residual disease setting.
1078-0432
3545-3555
Williams, Emily L.
f2650481-4f32-470a-b7fb-c78f026de16c
Dunn, Stuart N.
f1686545-1280-45d7-94af-b3b8c5ec0077
James, Sonya
764c80e3-5bea-4b34-a871-b43f87ef97b0
Johnson, Peter W.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Gray, Juliet C.
12d5e17c-97bb-4d6d-8fc4-3914b730ed42
Williams, Emily L.
f2650481-4f32-470a-b7fb-c78f026de16c
Dunn, Stuart N.
f1686545-1280-45d7-94af-b3b8c5ec0077
James, Sonya
764c80e3-5bea-4b34-a871-b43f87ef97b0
Johnson, Peter W.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Gray, Juliet C.
12d5e17c-97bb-4d6d-8fc4-3914b730ed42

Williams, Emily L., Dunn, Stuart N., James, Sonya, Johnson, Peter W., Cragg, Mark S., Glennie, Martin J. and Gray, Juliet C. (2013) Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model. Clinical Cancer Research, 19 (13), 3545-3555. (doi:10.1158/1078-0432.CCR-12-3226). (PMID:23649004)

Record type: Article

Abstract

PURPOSE: Neuroblastoma is one of the commonest extra-cranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models.

EXPERIMENTAL DESIGN: Neuroblastoma bearing mice were treated with mAb targeting 4-1BB, CD40 and CTLA-4 alone, or in combination with a peptide derived from the tumor antigen survivin (GWEDPPNDI). Survivin-specific immune response and therapeutic efficacy was assessed.

RESULTS: In the Neuro2a model, treatment of established tumor with either anti-4-1BB, anti-CD40 or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40-60% of mice. This is dependent on NK and CD8+ T cells and is associated with tumor CD8+ lymphocyte infiltrate. Successful therapy is achieved only if mAb is given to mice once tumors are established, suggesting dependence on sufficient tumor to provide antigen. In the more aggressive AgN2a and NXS2 models, single agent mAb therapy provides ineffective therapy. However if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination then 60% long term survival is achieved. This is associated with the generation of survivin-specific T cell immunity, which again is only demonstrated in the presence of tumor antigen.

CONCLUSIONS: These data suggest the combination of antigen and co-stimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal-residual disease setting.

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e-pub ahead of print date: 6 May 2013
Published date: 1 July 2013
Organisations: Cancer Sciences

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Local EPrints ID: 352382
URI: http://eprints.soton.ac.uk/id/eprint/352382
ISSN: 1078-0432
PURE UUID: 297515e1-bb03-4763-9f74-5f34f8d88c9c
ORCID for Peter W. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Juliet C. Gray: ORCID iD orcid.org/0000-0002-5652-4722

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Date deposited: 13 May 2013 11:10
Last modified: 15 Mar 2024 03:16

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Contributors

Author: Emily L. Williams
Author: Stuart N. Dunn
Author: Sonya James
Author: Mark S. Cragg ORCID iD
Author: Juliet C. Gray ORCID iD

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