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Tumor-targeted il-2 amplifies t cell-mediated immune response induced by gene therapy with single-chain il-12

Academic Article
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Overview

authors

  • Lode, H. N.
  • Xiang, R.
  • Duncan, S. R.
  • Theofilopoulos, Argyrios
  • Gillies, S. D.
  • Reisfeld, Ralph

publication date

  • 1999

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Induction, maintenance, and amplification of tumor-protective immunity after cytokine gene therapy is essential for the clinical success of immunotherapeutic approaches. We investigated whether this could be achieved by single-chain IL-12 (scIL-12) gene therapy followed by tumor-targeted IL-2 using a fusion protein containing a tumor-specific recombinant anti-ganglioside GD(2) antibody and IL-2 (ch14.18-IL-2) in a poorly immunogenic murine neuroblastoma model. Herein, we demonstrate the absence of liver and bone marrow metastases after a lethal challenge with NXS2 wild-type cells only in mice (five of six animals) vaccinated with scIL-12-producing NXS2 cells and given a booster injection of low-dose ch14.18-IL-2 fusion protein. This tumor-protective immunity was effective 3 months after initial vaccination, in contrast to control animals treated with a nonspecific fusion protein or an equivalent mixture of antibody and IL-2. Only vaccinated mice receiving the tumor-specific ch14.18-IL-2 fusion protein revealed a reactivation of CD8(+) T cells and subsequent MHC class I-restricted tumor target cell lysis in vitro. The sequential increase in the usage of TCR chains Vbeta11 and -13 in mouse CD8(+) T cells after vaccination and amplification with ch14.18-IL-2 suggests that the initial polyclonal CD8(+) T cell response is effectively boosted by targeted IL-2. In conclusion, we demonstrate that a successful boost of a partially protective memory T cell immune response that is induced by scIL-12 gene therapy could be generated by tumor-specific targeting of IL-2 with a ch14.18-IL-2 fusion protein. This approach could increase success rates of clinical cancer vaccine trials.

subject areas

  • Animals
  • Antibodies, Neoplasm
  • Antineoplastic Agents
  • CD8-Positive T-Lymphocytes
  • Cancer Vaccines
  • Disease Models, Animal
  • Gangliosides
  • Genetic Therapy
  • Immunotherapy
  • Interleukin-12
  • Interleukin-2
  • Mice
  • Neoplasm Transplantation
  • Neuroblastoma
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Tumor Cells, Cultured
  • Vaccination
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Identity

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.96.15.8591

PubMed ID

  • 10411920
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Additional Document Info

start page

  • 8591

end page

  • 8596

volume

  • 96

issue

  • 15

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