Naxitamab Activity in Neuroblastoma Cells Is Enhanced by Nanofenretinide and Nanospermidine

Abstract

Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is also expressed in neurons, skin melanocytes, and peripheral nerve fibers. Immunotherapy with monoclonal anti-GD2 antibodies has a proven efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. However, the strong neuro-toxicity associated with anti-GD2 antibodies administration has hindered, until now, the possibility for dose-escalation and protracted use, thus restraining their therapeutic potential. Strategies to increase the efficacy of anti-GD2 antibodies are actively sought, with the aim to enable chronic treatments that could eradicate minimal residual disease and subsequent relapses, often occurring after treatment. Here, we report that Nanofenretinide and Nanospermidine improved the expression of GD2 in neuroblastoma cells (CHP-134) and provided different effects in combination with the anti-GD2 antibody naxitamab. In particular, Nanofenretinide significantly increased the cytotoxic effect of naxitamab while Nanospermidine inhibited cell motility at extents proportional to naxitamab concentration. In neuroblastoma cells characterized by a low and heterogeneous basal expression of GD2, such as SH-SY5Y, which may represent the cell heterogeneity in tumors after chemotherapy, both Nanofenretinide and Nanospermidine increased GD2 expression in approximately 50% of cells, thus shifting the tumor population towards improved sensitivity to anti-GD2 antibodies.

Nano-fenretinide demonstrates remarkable activity in acute promyeloid leukemia cells

“…Again, the NF concentrations active in HL60R cells corresponded to FEN levels easily achievable in vivo, as demonstrated by NF administration in mouse models of solid tumors [11][12][13][14][15][16] .…”

“…This system is spontaneously formed by dispersing in water an amphiphilic mixture of phosphatidylcholine, glyceryl tributyrate and 2-hydroxypropyl beta cyclodextrin. NF has been studied in vitro and in vivo in a wide range of tumor models [11][12][13][14][15][16] . The results demonstrated high bioavailability and antitumor activity either by intravenous and oral administration [11][12][13][14][15][16] .…”

“…NF has been studied in vitro and in vivo in a wide range of tumor models [11][12][13][14][15][16] . The results demonstrated high bioavailability and antitumor activity either by intravenous and oral administration [11][12][13][14][15][16] . At the best of our knowledge, no studies have been performed in hematologic malignancies.…”

“…The nanomicelles were obtained spontaneously by dispersing in PBS a mixture of phospholipids, glyceryl tributyrate, 2-hydroxypropyl beta cyclodextrin, FEN or ATRA in defined molar ratios. The amphiphilic character of the mixture triggers a supramolecular assembly in an aqueous environment, with formation of nanomicelles that entrap FEN or ATRA [11][12][13][14][15][16] . In Fig.…”

Biology of GD2 ganglioside: implications for cancer immunotherapy

“…As such, other GD2-positive cancer may benefit from strategies to increase antigen expression to levels similar to neuroblastoma. Different compounds may achieve this effect, such as epigenetic modulators (HDAC or EZH2 inhibitors), cytokines (IFNγ, TNFα, IL-4) which may additionally potentiate immune effectors, retinoids (Fenretinide), or polyamine (nanospermidine) as more recently described ( Hoon et al, 1991a ; Hoon et al, 1991b ; Shibina et al, 2013 ; Kroesen et al, 2016 ; van den Bijgaart et al, 2019 ; Kailayangiri et al, 2019 ; Mabe et al, 2022 ; Galassi et al, 2023 ). Identifying the most suitable patients and the optimal timing for these approaches should also be taken into consideration to improve the patients’ outcome.…”