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Systematic Targeting of GD2-Positive Neuroblastoma Tumors With a Photooncolytic Phage Nanovector Platform
Suleman Khan Zadran1,2,3, Nicola Facchinello1,4, Piergiuseppe De Rosa1
1Department of Pharmacy and Biotechnology Alma Mater Studiorum - University of Bologna, via Francesco Selmi 3, Bologna, 40126, Italy.
Abstract:
Disialoganglioside-GD2 is a key molecular target for Neuroblastoma (NB) immunotherapy based on the employment of GD2-targeting antibodies. However, about 50% of treated patients can experience tumor relapse due to limited immune-mediated cytotoxicity and poor antibody penetration into tumors. To address this problem, a tumor-penetrating photo-oncolytic phage nanovector platform is genetically and chemically developed that selectively targets GD2-expressing NB cells. The phage bioconjugates, functionalized with different photosensitizers, result in specific and selective oncolysis of GD2-positive NB cells upon light irradiation, without affecting GD2-negative ones. The photo-oncolytic phage vectors are shown to deeply penetrate into GD2-positive tumor spheroids in vitro, and to cross biological barriers in a zebrafish xenograft model, maintaining their ablation specificity upon irradiation. Finally, to overcome resistance from GD2 loss, often linked to poor prognosis, a CRISPRa strategy is introduced to reactivate GD2 expression in GD2-negative cells. The approach offers a minimally invasive and highly effective strategy, addressing unmet needs in NB therapy.
Insights
This study introduces a novel phage nanovector platform for neuroblastoma (NB) immunotherapy. The platform targets GD2-expressing NB cells, enhances tumor penetration, and overcomes treatment resistance for improved patient outcomes.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Immunotherapy
Background:
- Disialoganglioside-GD2 (GD2) is a primary target for neuroblastoma (NB) immunotherapy.
- Current GD2-targeting antibodies face challenges like limited tumor penetration and resistance, leading to relapse in ~50% of patients.
Purpose of the Study:
- To develop an advanced nanovector platform for enhanced NB therapy.
- To improve antibody penetration and overcome resistance mechanisms in NB treatment.
Main Methods:
- Genetically and chemically engineered photo-oncolytic phage nanovectors targeting GD2-positive NB cells.
- Functionalization of phage bioconjugates with photosensitizers for light-activated oncolysis.
- In vitro and in vivo (zebrafish xenograft model) evaluation of tumor penetration and specificity.
- CRISPR activation (CRISPRa) strategy to restore GD2 expression in resistant cells.
Main Results:
- Phage nanovectors selectively targeted and induced oncolysis in GD2-positive NB cells upon light irradiation.
- Demonstrated deep penetration into tumor spheroids and crossing of biological barriers in vivo.
- Specificity maintained upon irradiation, sparing GD2-negative cells.
- CRISPRa successfully reactivated GD2 expression in GD2-negative cells.
Conclusions:
- The developed photo-oncolytic phage nanovector platform offers a minimally invasive and effective strategy for NB immunotherapy.
- This approach addresses critical limitations of current therapies, including poor penetration and resistance.
- The combined strategy of phage delivery and GD2 re-expression presents a promising avenue for treating neuroblastoma.
