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GD2-targeted immunotherapy in pediatric bone sarcomas: a systematic review of emerging strategies and combination
Elisa Tirtei1,2, Sofia Poggi Longostrevi1,2, Sabrina Bombaci1
1Pediatric Onco-Hematology Department, Regina Margherita Children's Hospital, Turin, Italy.
Introduction:
Primary bone sarcomas, including Osteosarcoma (OS) and Ewing sarcoma (ES), are rare pediatric malignancies with limited therapeutic advances over recent decades and poor outcomes, especially for patients with metastatic and refractory/relapsed disease. Disialoganglioside 2 (GD2) has emerged as a promising immunotherapeutic target due to its high expression in pediatric bone sarcomas and its role in tumor progression and treatment resistance. This systematic review summarizes current evidence on GD2-targeted therapies and combination strategies in pediatric bone sarcomas.
Methods:
A systematic review was conducted according to PRISMA 2020 guidelines using PubMed, Embase, Web of Science, and ClinicalTrials.gov. Preclinical and clinical studies investigating GD2-targeted therapies in pediatric bone sarcomas were included, together with registered clinical trials.
Results:
Twenty-six studies met inclusion criteria, including 17 preclinical and 9 clinical studies, alongside 15 ongoing clinical trials. Preclinical evidence consistently demonstrated antitumor activity of GD2-directed approaches, including monoclonal antibodies (mAbs), CAR-T cells, bispecific antibodies, and radio-immunotherapy. Combination strategies, particularly anti-GD2 mAbs with chemotherapy, enhanced antitumor efficacy through induction of apoptosis, activation of endoplasmic reticulum stress pathways, and inhibition of tumor invasiveness. Clinical evidence, although limited and heterogeneous, suggested encouraging activity of Dinutuximab beta-based chemo-immunotherapy, especially in ES. Several clinical trials are ongoing, mainly early-phase and focusing on relapsed or refractory diseases.
Discussion:
GD2 represents a biologically relevant and clinically promising target in pediatric bone sarcomas. However, major translational challenges remain, including limited clinical data, heterogeneous study designs, and the lack of standardized assays for GD2 expression assessment. Further collaborative international studies are needed to optimize patient selection and accelerate the development of GD2-targeted combination immunotherapy strategies.
Insights
Disialoganglioside 2 (GD2) shows promise for treating pediatric bone sarcomas like Osteosarcoma and Ewing sarcoma. Combination immunotherapies targeting GD2 demonstrate antitumor activity, but further research is needed to overcome translational challenges.
Area of Science:
- Oncology
- Immunotherapy
- Pediatric Malignancies
Background:
- Primary bone sarcomas (Osteosarcoma, Ewing sarcoma) are rare pediatric cancers with poor outcomes, especially in advanced stages.
- Disialoganglioside 2 (GD2) is highly expressed in these tumors and is a potential target for immunotherapy.
- Current therapeutic advances for pediatric bone sarcomas are limited, necessitating novel treatment strategies.
Purpose of the Study:
- To systematically review current evidence on GD2-targeted therapies and combination strategies for pediatric bone sarcomas.
- To summarize preclinical and clinical findings on GD2-directed approaches.
- To identify ongoing research and future directions in GD2 immunotherapy for these cancers.
Main Methods:
- Systematic review conducted following PRISMA 2020 guidelines.
- Searches performed in PubMed, Embase, Web of Science, and ClinicalTrials.gov.
- Inclusion of preclinical studies, clinical studies, and registered clinical trials investigating GD2-targeted therapies.
Main Results:
- Seventeen preclinical studies showed consistent antitumor activity for GD2-targeted therapies (mAbs, CAR-T, etc.).
- Nine clinical studies, particularly Dinutuximab beta-based chemo-immunotherapy, showed encouraging activity in Ewing sarcoma.
- Combination strategies, especially anti-GD2 mAbs with chemotherapy, enhanced efficacy via apoptosis and reduced tumor invasiveness.
Conclusions:
- GD2 is a biologically relevant and promising target for pediatric bone sarcomas.
- Translational challenges include limited clinical data, study heterogeneity, and lack of standardized GD2 assessment.
- Collaborative international studies are crucial to optimize patient selection and advance GD2-targeted combination immunotherapies.
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