Neuroblastoma regression and immunity induced by transgenic expression of interleukin-12.
OBJECTIVE
Interleukin-12 (IL-12) is a cytokine with potent antitumor effects. The authors sought to assess its capacity to increase tumor immunogenicity when expressed by tumor cells in a murine model of neuroblastoma.


METHODS
Syngeneic A/J mice were inoculated subcutaneously with 2 x 10(6) cells from a murine neuroblastoma-derived cell line (neuro-2a). In situ transduction of the neuroblastoma cells was achieved by intratumoral injection of an adenoviral vector encoding both subunits of the murine IL-12 heterodimer. Growth of the IL-12 gene-modified tumor cells was compared with untreated neuro-2a cells. Tumor immunity was assessed by rechallenging mice that had rejected their tumor with unmodified neuroblastoma cells. The contribution of cytotoxic T lymphocytes (CTLs) was evaluated through cytotoxicity assays.


RESULTS
Eighteen (72%) of 25 tumor-bearing mice treated with the mlL-12 adenoviral vector exhibited tumor regression, with 12 mice (48%) completely rejecting their tumors over 2 to 3 weeks. None of the mice that had rejected their tumor and were rechallenged with unmodified neuro-2a cells subsequently developed new tumors. Pooled splenocytes from mice rejecting their tumors showed significant tumor killing (>20% cytolysis) in vitro in 51Cr release assays.


CONCLUSIONS
Adenoviral-mediated IL-12 expression by tumor cells in a murine neuroblastoma model produced a significant antitumor response. Most treated tumors demonstrated at least transient regression, whereas many completely regressed. Cured mice exhibited protective immunity and CTL activity against the tumor. These data confirm the immunomodulatory efficacy of IL-12 as part of a vaccine-based antineuroblastoma strategy.
Davidoff
A M
AM
Department of Surgery, St Jude Children's Research Hospital and University of Tennessee, Memphis 38105, USA.
Kimbrough
S A
SA
Ng
C Y
CY
Shochat
S J
SJ
Vanin
E F
EF
D000256:Adenoviridae; D000276:Adjuvants, Immunologic; D000818:Animals; D003602:Cytotoxicity, Immunologic; D015316:Genetic Therapy; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D009447:Neuroblastoma / Q000276:immunology* / Q000628:therapy*; D012074:Remission Induction; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D018664:Interleukin-12