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Sequential Immunogene Therapy with Interleukin-12– and Interleukin-15–Engineered Neuroblastoma Cells Cures Metastatic Disease in Syngeneic Mice

¹ Laboratory of Immunopharmacology, Istituto Nazionale per la Ricerca sul Cancro; Laboratories of ² Clinical and Experimental Immunology, ³ Pathology, and ⁴ Oncology, Gaslini Institute, Genoa, Italy and ⁵ Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy

Requests for reprints: Silvano Ferrini, Laboratory of Immunopharmacology, Istituto Nazionale per la Ricerca sul Cancro, Largo Benzi 10, 16132 Genoa, Italy. Phone: 39-010-5737372; Fax: 39-010-5737374; E-mail: silvano.ferrini{at}istge.it.

Purpose: To investigate the potential synergistic effects of Neuro2a neuroblastoma cells engineered with IL-12 and/or IL-15 genes in improving survival of syngeneic mice bearing neuroblastoma metastatic disease.

Experimental Design: Neuro2a cells engineered with interleukin (IL)-12 (Neuro2a/IL-12), IL-15 (Neuro2a/IL-15), or both cytokines (Neuro2a/IL-12/IL-15) were injected s.c. in syngeneic A/J mice challenged i.v. with Neuro2a parental cells (Neuro2apc) using different schedules of administration in either preventive or therapeutic settings.

Results: A single injection of Neuro2a/IL-12 or Neuro2a/IL-15 cells induced resistance to a subsequent i.v. Neuro2apc challenge in 45% and 28% of mice, respectively. Neuro2a/IL-12/IL-15 cells protected 28% of mice, showing no synergistic effect. However, sequential vaccination with Neuro2a/IL-12 (day –30) followed by Neuro2a/IL-15 (day –15) protected 71% of mice from subsequent challenge with Neuro2apc. A single dose of Neuro2a/IL-12 prolonged the mean survival time of mice bearing established metastatic neuroblastoma from 21 ± 3 to 46 ± 27 days but failed to cure mice, whereas Neuro2a/IL-15 or Neuro2a/IL-12/IL-15 were ineffective. However, sequential vaccination with Neuro2a/IL-12 (day +3) followed by Neuro2a/IL-15 (day +13) cured 43% of mice as assessed by histologic analysis of different organs from long-term surviving mice. CTL activity against Neuro2apc cells was observed in splenocytes from treated mice, and CD8⁺ T-cell depletion abrogated the therapeutic effect of vaccination.

Conclusions: Sequential vaccination with IL-12- and IL-15-engineered neuroblastoma cells induced optimal preventive and therapeutic effects, which may be related to the Th1 priming effect of IL-12 followed by the enhancement of CD8⁺ T-cell responses and their maintenance mediated by IL-15.

Key Words: Cytotoxic T-lymphocytes • neuroblastoma • CD8⁺ T cells • transfection • cytokines

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