Immunotherapy of neuroblastoma by an Interleukin-21-secreting cell vaccine involves survivin as antigen

Michela Croce, Raffaella Meazza, Anna M. Orengo, Marina Fabbi, Martina Borghi, Domenico Ribatti, Beatrice Nico, Barbara Carlini, Vito Pistoia, Maria Valeria Corrias, Silvano Ferrini

Research output: Contribution to journalArticle

Abstract

Aim: IL-21 is the most recently identified member of the IL-2 cytokine family. Here we studied the therapeutic efficacy of IL-21-gene-modified cells (Neuro2a/IL-21) in a syngeneic metastatic neuroblastoma (NB) model. Materials and methods: Neuro2a/IL-21 cells were tested as subcutaneous (sc) vaccine both in prophylactic and therapeutic settings. Depletion studies, cytotoxicity assay and immunohistochemical analyses were carried out to evaluate the mechanisms involved in tumor rejection. Results: When injected sc in syngeneic A/J mice viable Neuro2a/IL-21 cells were rejected and induced resistance to a subsequent iv challenge with Neuro2a parental cells (Neuro2a/pc), suggesting the involvement of an immune response. More importantly, in mice bearing Neuro2a/pc micrometastases, a single sc injection of Neuro2a/IL-21 cells significantly increased the mean tumor-free survival of treated animals (43 vs. 22 days) and cured 14% of them. The administration of two or three doses of Neuro2a/IL-21 cell vaccine further increased the mean survival time to 54 and 75 days, and the cure rate to 27 and 33%, respectively, whereas the use of unmodified Neuro2a or mock-transfected cells had no effect. In vivo cell subset depletion and a Winn-assay indicated the involvement of CD8 + CTLs. Immunohistochemical analysis indicated a reduction of CD31+ and VEGFR2+ microvessels in late metastases from therapeutically vaccinated mice. A role of survivin as antigen was suggested by in vitro assays using survivin-synthetic CTL-epitopes. Conclusions: Our present data indicate that IL-21-secreting NB cells are effective as therapeutic vaccine in mice bearing metastatic NB, through a specific CTL response involving survivin as antigen, and suggest a potential interest for IL-21 in NB immuno-gene therapy.

Original languageEnglish
Pages (from-to)1625-1634
Number of pages10
JournalCancer Immunology, Immunotherapy
Volume57
Issue number11
DOIs
Publication statusPublished - Nov 2008

Fingerprint

Neuroblastoma
Immunotherapy
Vaccines
Antigens
interleukin-21
Neoplasm Micrometastasis
Subcutaneous Injections
Microvessels
Genetic Therapy
Interleukin-2
Epitopes
Neoplasms
Therapeutics
Cytokines
Neoplasm Metastasis

Keywords

  • Cancer vaccine
  • Interleukin-21
  • Neuroblastoma
  • Survivin

ASJC Scopus subject areas

  • Cancer Research
  • Immunology
  • Oncology

Cite this

Immunotherapy of neuroblastoma by an Interleukin-21-secreting cell vaccine involves survivin as antigen. / Croce, Michela; Meazza, Raffaella; Orengo, Anna M.; Fabbi, Marina; Borghi, Martina; Ribatti, Domenico; Nico, Beatrice; Carlini, Barbara; Pistoia, Vito; Corrias, Maria Valeria; Ferrini, Silvano.

In: Cancer Immunology, Immunotherapy, Vol. 57, No. 11, 11.2008, p. 1625-1634.

Research output: Contribution to journalArticle

Croce, Michela ; Meazza, Raffaella ; Orengo, Anna M. ; Fabbi, Marina ; Borghi, Martina ; Ribatti, Domenico ; Nico, Beatrice ; Carlini, Barbara ; Pistoia, Vito ; Corrias, Maria Valeria ; Ferrini, Silvano. / Immunotherapy of neuroblastoma by an Interleukin-21-secreting cell vaccine involves survivin as antigen. In: Cancer Immunology, Immunotherapy. 2008 ; Vol. 57, No. 11. pp. 1625-1634.
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abstract = "Aim: IL-21 is the most recently identified member of the IL-2 cytokine family. Here we studied the therapeutic efficacy of IL-21-gene-modified cells (Neuro2a/IL-21) in a syngeneic metastatic neuroblastoma (NB) model. Materials and methods: Neuro2a/IL-21 cells were tested as subcutaneous (sc) vaccine both in prophylactic and therapeutic settings. Depletion studies, cytotoxicity assay and immunohistochemical analyses were carried out to evaluate the mechanisms involved in tumor rejection. Results: When injected sc in syngeneic A/J mice viable Neuro2a/IL-21 cells were rejected and induced resistance to a subsequent iv challenge with Neuro2a parental cells (Neuro2a/pc), suggesting the involvement of an immune response. More importantly, in mice bearing Neuro2a/pc micrometastases, a single sc injection of Neuro2a/IL-21 cells significantly increased the mean tumor-free survival of treated animals (43 vs. 22 days) and cured 14{\%} of them. The administration of two or three doses of Neuro2a/IL-21 cell vaccine further increased the mean survival time to 54 and 75 days, and the cure rate to 27 and 33{\%}, respectively, whereas the use of unmodified Neuro2a or mock-transfected cells had no effect. In vivo cell subset depletion and a Winn-assay indicated the involvement of CD8 + CTLs. Immunohistochemical analysis indicated a reduction of CD31+ and VEGFR2+ microvessels in late metastases from therapeutically vaccinated mice. A role of survivin as antigen was suggested by in vitro assays using survivin-synthetic CTL-epitopes. Conclusions: Our present data indicate that IL-21-secreting NB cells are effective as therapeutic vaccine in mice bearing metastatic NB, through a specific CTL response involving survivin as antigen, and suggest a potential interest for IL-21 in NB immuno-gene therapy.",
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T1 - Immunotherapy of neuroblastoma by an Interleukin-21-secreting cell vaccine involves survivin as antigen

AU - Croce, Michela

AU - Meazza, Raffaella

AU - Orengo, Anna M.

AU - Fabbi, Marina

AU - Borghi, Martina

AU - Ribatti, Domenico

AU - Nico, Beatrice

AU - Carlini, Barbara

AU - Pistoia, Vito

AU - Corrias, Maria Valeria

AU - Ferrini, Silvano

PY - 2008/11

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N2 - Aim: IL-21 is the most recently identified member of the IL-2 cytokine family. Here we studied the therapeutic efficacy of IL-21-gene-modified cells (Neuro2a/IL-21) in a syngeneic metastatic neuroblastoma (NB) model. Materials and methods: Neuro2a/IL-21 cells were tested as subcutaneous (sc) vaccine both in prophylactic and therapeutic settings. Depletion studies, cytotoxicity assay and immunohistochemical analyses were carried out to evaluate the mechanisms involved in tumor rejection. Results: When injected sc in syngeneic A/J mice viable Neuro2a/IL-21 cells were rejected and induced resistance to a subsequent iv challenge with Neuro2a parental cells (Neuro2a/pc), suggesting the involvement of an immune response. More importantly, in mice bearing Neuro2a/pc micrometastases, a single sc injection of Neuro2a/IL-21 cells significantly increased the mean tumor-free survival of treated animals (43 vs. 22 days) and cured 14% of them. The administration of two or three doses of Neuro2a/IL-21 cell vaccine further increased the mean survival time to 54 and 75 days, and the cure rate to 27 and 33%, respectively, whereas the use of unmodified Neuro2a or mock-transfected cells had no effect. In vivo cell subset depletion and a Winn-assay indicated the involvement of CD8 + CTLs. Immunohistochemical analysis indicated a reduction of CD31+ and VEGFR2+ microvessels in late metastases from therapeutically vaccinated mice. A role of survivin as antigen was suggested by in vitro assays using survivin-synthetic CTL-epitopes. Conclusions: Our present data indicate that IL-21-secreting NB cells are effective as therapeutic vaccine in mice bearing metastatic NB, through a specific CTL response involving survivin as antigen, and suggest a potential interest for IL-21 in NB immuno-gene therapy.

AB - Aim: IL-21 is the most recently identified member of the IL-2 cytokine family. Here we studied the therapeutic efficacy of IL-21-gene-modified cells (Neuro2a/IL-21) in a syngeneic metastatic neuroblastoma (NB) model. Materials and methods: Neuro2a/IL-21 cells were tested as subcutaneous (sc) vaccine both in prophylactic and therapeutic settings. Depletion studies, cytotoxicity assay and immunohistochemical analyses were carried out to evaluate the mechanisms involved in tumor rejection. Results: When injected sc in syngeneic A/J mice viable Neuro2a/IL-21 cells were rejected and induced resistance to a subsequent iv challenge with Neuro2a parental cells (Neuro2a/pc), suggesting the involvement of an immune response. More importantly, in mice bearing Neuro2a/pc micrometastases, a single sc injection of Neuro2a/IL-21 cells significantly increased the mean tumor-free survival of treated animals (43 vs. 22 days) and cured 14% of them. The administration of two or three doses of Neuro2a/IL-21 cell vaccine further increased the mean survival time to 54 and 75 days, and the cure rate to 27 and 33%, respectively, whereas the use of unmodified Neuro2a or mock-transfected cells had no effect. In vivo cell subset depletion and a Winn-assay indicated the involvement of CD8 + CTLs. Immunohistochemical analysis indicated a reduction of CD31+ and VEGFR2+ microvessels in late metastases from therapeutically vaccinated mice. A role of survivin as antigen was suggested by in vitro assays using survivin-synthetic CTL-epitopes. Conclusions: Our present data indicate that IL-21-secreting NB cells are effective as therapeutic vaccine in mice bearing metastatic NB, through a specific CTL response involving survivin as antigen, and suggest a potential interest for IL-21 in NB immuno-gene therapy.

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KW - Interleukin-21

KW - Neuroblastoma

KW - Survivin

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