Fenretinide (4-HPR) as immunostimulator of the antibody-dependent (ADCC) and antibody-independent NK cell mediated cytotoxicity (AICC) on neuroblastoma

I Lichy; A Stermann; D Seidel; N Siebert; HN Lode

doi:10.1055/s-0033-1343658

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Klin Padiatr 2013; 225 - A41
DOI: 10.1055/s-0033-1343658

Fenretinide (4-HPR) as immunostimulator of the antibody-dependent (ADCC) and antibody-independent NK cell mediated cytotoxicity (AICC) on neuroblastoma

I Lichy ¹, A Stermann ¹, D Seidel ¹, N Siebert ¹, HN Lode ¹

¹University Medicine Greifswald Pediatric Hematology/Oncology, Greifswald,. Germany

Congress Abstract

Introduction: A current approach to consolidate remissions in the treatment of neuroblastoma (NB) consists of an anti-GD₂-directed immunotherapy plus cytokines in combination with 13-cis retinoic acid. Fenretinide (4-HPR) is a synthetic derivative of retinoic acid and it is in clinical development for the treatment of high-risk NB patients. Since 4-HPR induces apoptosis mainly via the accumulation of ceramides, which are degraded to GD₂, we evaluated its effect on anti-GD₂-directed immunotherapies.

Methods/Results: We demonstrate that increased GD₂ expression by 4-HPR results in improved ch14.18 mediated ADCC by NK cells. Interestingly, also AICC was elevated indicating an additional immunostimulatory effect of 4-HPR. To this end, we report the effect of 4-HPR on increased expression of death receptors on the target cells (Fas, TRAIL-R2) as well as of the activating NK cell receptors NKG2D and DNAM-1. Furthermore, preliminary results indicating an increase of the stress induced ligands MIC A/B, ULBP-1 and Nectin-2 emphasizing the immunostimulatory effect.

Conclusion: These findings provide an important baseline for the combination of 4-HPR and passive immunotherapy in future clinical trials for high-risk NB patients.