作者: Petridou, Eleni Th. ; Hatzipantelis, Emmanuel ; Karalexi, Maria A. ; Bouka, Panagiota ; Servitzoglou, Marina ; Ntzani, Evangelia ; Stefanaki, Kalliopi ; Polychronopoulou, Sofia ; Papadakis, Vassilios ; Baka, Margaret ; Themistocleous, Marios S. ; Strantzia, Katerina ; Shamanskaya, Tatyana ; Kantzanou, Maria ; Dana, Helen ; Malama, Astero ; Česen Mazič, Maja ; Stiakaki, Eftichia ; Panagopoulou, Paraskevi ; Kourti, Maria ; Moschovi, Maria ; Kachanov, Denis ; Dessypris, Nick

The prognosis of children with neuroblastoma (NBL) can be dismal with significant variations depending on the stage and biology of the tumor. We assessed the event-free (EFS) and overall (OS) survival using harmonized data from three Southern-Eastern European (SEE) countries. Data for 520 incident NBL cases (2009–2018) were collected from Greece, Slovenia and Russia. Kaplan–Meier curves were fitted, and EFS/OS were derived from Cox proportional models by study variables including the protocol-based risk-group (low/observation, intermediate, high). Over one-third of cases were coded in the high-risk group, of which 23 children (4.4%) received treatment with anti-ganglioside 2 (GD2) mAb. Survival rates were inferior in older (OS 5-year; 1.5–4.9 years: 61%; EFS 5-year; 1.5–4.9 years: 48%) compared to children younger than 1.5 years (OS 5-year; <1.5 years: 91%; EFS 5-year; <1.5 years: 78%). Predictors of poor OS included stage 4 (hazard ratio, HROS: 18.12, 95% confidence intervals, CI: 3.47–94.54), N-myc amplification (HROS: 2.16, 95% CI: 1.40–3.34), no surgical excision (HROS: 3.27, 95% CI: 1.91–5.61) and relapse/progression (HROS: 5.46, 95% CI: 3.23–9.24). Similar unfavorable EFS was found for the same subsets of patients. By contrast, treatment with anti-GD2 antibody in high-risk patients was associated with decreased risk of death or unfavorable events (HROS: 0.11, 95% CI: 0.02–0.79; HREFS: 0.19, 95% CI: 0.07–0.52). Our results confirm the outstanding prognosis of the early NBL stages, especially in children <1.5 years, and the improved outcomes of the anti-GD2 treatment in high-risk patients. Ongoing high-quality clinical cancer registration is needed to ensure comparability of survival across Europe and refine our understanding of the NBL biology.

2022-09-01·Clinical cancer research : an official journal of the American Association for Cancer Research

Anti-GD2 Antibodies Conjugated to IL15 and IL21 Mediate Potent Antitumor Cytotoxicity against Neuroblastoma

Article

作者: Abbas, Shahroze ; Kelly, Michael C. ; Seibert, Charlie ; Zhang, Xiyuan ; Nguyen, Rosa ; Thiele, Carol J. ; Shern, Jack F. ; Sun, Ming

Abstract:

Purpose::

Half of the patients with high-risk neuroblastoma who receive GD2-targeted mAb do not achieve long-term remissions. Recently, the antibody hu14.18 has been linked to IL2 (hu14.18-IL2) to enhance its efficacy and shown promising preclinical and clinical activity. We developed two new immunocytokines (IC) by linking two other γc cytokines, IL15 and IL21, to hu14.18. The purpose of this study was to compare hu14.18-IL15 and -IL21 with hu14.18-IL2 in their ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) against neuroblastoma.

Experimental Design::

We assessed ADCC of hu14.18-IL15 and -IL2 (human cytokines, cross-reactive to mouse) against GD2low and GD2high neuroblastoma cell lines in vitro. T-cell–deficient mice with orthotopic patient-derived xenografts (PDX) and immunocompetent mice with transplantable orthotopic neuroblastoma were used to test all three ICs, including hu14.18-IL21 (murine IL21, not cross-reactive to human). Mechanistic studies were performed using single-cell RNA-sequencing (scRNA-seq).

Results::

hu14.18-IL15 and hu14.18-IL2 mediated equivalent in vitro ADCC by human NK cells. When combined with chemotherapy, all three ICs similarly controlled the growth of PDXs in nude mice with murine NK effector cells. However, hu14.18-IL15 and -IL21 outperformed hu14.18-IL2 in immunocompetent mice with syngeneic neuroblastoma, inducing complete tumor regressions and extending survival. scRNA-seq data revealed an increase in CD8+ T cells and M1 tumor-associated macrophages and decreased regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment.

Conclusions::

Hu14.18-IL15 and Hu14.18-IL21 exhibit robust preclinical activity, warranting further consideration for clinical testing in patients with GD2-expressing neuroblastoma.

2021-04-01·Cancer letters1区 · 医学

The glycosphingolipid GD2 as an effective but enigmatic target of passive immunotherapy in children with aggressive neuroblastoma (HR-NBL)

1区 · 医学

Review

作者: Rovigatti, Ugo

Neuroblastoma (NBL), the most frequent and lethal pediatric cancer of children in pre-school age, is considered enigmatic in view of its extreme heterogeneity, from spontaneous regression in the IV-S form to incurable disease in approx. 40% of cases (High Risk, HR-NBL). It has an embryonal origin and a very heterogeneous genomic landscape, hampering the success of targeted strategies. The glycosphingolipid GD2 was shown to be expressed on NBL cells and utilized as target for passive immunotherapy with anti-GD2 antibodies (GD2-IMT). An international protocol was established with GD2-IMT, which increases remission length and survival in HR-NBL. By reviewing the different biological and molecular aspects of NBL and GD2-IMT, this mini-review questions the present lack of association between GD2-IMT and the underlying molecular landscape. The alternative model of Micro-Foci inducing virus (MFV) is presented, since MFV infection can induce extensive genomic aberrations (100X NMYC DNA-amplification). Since this family of viruses uses molecules for cell penetration similar to GD2 (i.e., GM2), it is hypothesized that GD2 is the port-of-entry for MFV and that success of anti-GD2 therapies is also associated to inhibition of this clastogenic virus in HR-NBL.

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