Fractalkine gene therapy for neuroblastoma is more effective in combination with targeted IL-2.
The induction of tumor protective immunity against neuroblastoma remains a major challenge for active immunotherapy. Fractalkine is a unique Th1 CX3C chemokine known to induce adhesion and migration of leukocytes mediated by both, a membrane-bound and soluble form, respectively. Here, we tested the hypothesis that chemokine gene therapy with fractalkine (FKN) induces an effective anti-neuroblastoma immune response amplified by targeted IL-2 using the anti-GD2 antibody ch14.18 fused with IL-2 (ch14.18-IL-2). For this purpose, NXS2 cells were genetically engineered to stably produce murine FKN (NXS2-FKN). Transcription and expression of the mFKN gene in tumor tissue of mice inoculated with NXS2-FKN cells were demonstrated in vivo. Importantly, mFKN exhibited a reduction in primary tumor growth and spontaneous liver metastases in syngenic A/J mice. This effect was boosted by targeted IL-2 using small non-curative doses of ch14-18-IL-2. The amplification of the FKN induced immune response was specific, since a non-specific antibody-IL-2 fusion protein ch225-IL-2 was ineffective. In summary, we demonstrated for the first time that chemokine gene therapy is amplified by targeted IL-2 suggesting a combination of both strategies as an adjuvant therapy for neuroblastoma.
Zeng
Yan
Y
Charite Children's Hospital, Campus Virchow, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
Jiang
Jikai
J
Huebener
Nicole
N
Wenkel
Jens
J
Gaedicke
Gerhard
G
Xiang
Rong
R
Lode
Holger N
HN
D000818:Animals; D001483:Base Sequence; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000235:genetics*; D017931:DNA Primers; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000556:secondary; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000628:therapy*
C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515539:Cx3cl1 protein, mouse; D017931:DNA Primers; D007376:Interleukin-2; D008565:Membrane Proteins