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Arming AAV9 with a Single-Chain Fragment Variable Antibody Against PD-1 for Systemic Glioblastoma Therapy
Semer Maksoud1,2,3, Markus W Schweiger4,5,6,7, Elie I Tabet4,5
1Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA. smaksoud@mgh.harvard.edu.
Abstract:
Glioblastoma (GBM) is a highly aggressive brain cancer with a low survival rate, prompting the exploration of novel therapeutic strategies. Immune checkpoint inhibitors have shown promise in cancer treatment but are associated with immune-related toxicities and brain penetration. Here, we present a targeted approach using an adeno-associated virus serotype 9 (AAV9) to systemically deliver a single-chain fragment variable antibody against PD-1 (scFv-PD-1) into the tumor microenvironment (TME). Single-cell RNA sequencing analysis revealed robust PD-1 expression in GBM TME, predominantly on T cells. AAV9-scFv-PD-1 expressed and secreted scFv-PD-1, which effectively binds to PD-1. Systemic administration of AAV9-scFv-PD-1 in an immunocompetent GBM mouse model resulted in a robust cytolytic T-cell activation at the tumor site, marked by accumulation of IFN-γ and Granzyme B, leading to a significant reduction in tumor growth. Importantly, AAV9-scFv-PD-1 treatment conferred a survival benefit, highlighting its therapeutic potential. This study demonstrates the feasibility of systemically delivered AAV9-mediated local expression of scFv-PD-1 for targeted immunotherapy in GBM and warrants further investigation for clinical translation.
Insights
A novel adeno-associated virus serotype 9 (AAV9) delivery system targets glioblastoma (GBM) by expressing an anti-PD-1 antibody. This immunotherapy approach activates T-cells, reduces tumor growth, and improves survival in preclinical models.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Gene Therapy
Background:
- Glioblastoma (GBM) is an aggressive brain cancer with poor prognosis.
- Current immunotherapies face challenges with toxicity and brain penetration.
- Targeted delivery of immune checkpoint inhibitors is needed for GBM treatment.
Purpose of the Study:
- To develop a targeted immunotherapy for GBM using adeno-associated virus serotype 9 (AAV9) to deliver a PD-1 inhibitor.
- To evaluate the efficacy of AAV9-mediated delivery of a single-chain fragment variable antibody against PD-1 (scFv-PD-1) in a GBM model.
Main Methods:
- Single-cell RNA sequencing to analyze PD-1 expression in the GBM tumor microenvironment (TME).
- Systemic administration of AAV9-scFv-PD-1 in an immunocompetent GBM mouse model.
- Assessment of T-cell activation, cytokine production (IFN-γ), and tumor growth.
Main Results:
- High PD-1 expression was confirmed on T cells within the GBM TME.
- AAV9-scFv-PD-1 successfully expressed and secreted functional scFv-PD-1, binding to PD-1.
- Treatment led to significant cytolytic T-cell activation, increased IFN-γ and Granzyme B levels, reduced tumor growth, and improved survival.
Conclusions:
- Systemic AAV9 delivery enables localized expression of scFv-PD-1 within the GBM TME.
- This targeted immunotherapy approach shows significant therapeutic potential for GBM.
- Further investigation is warranted for clinical translation of this AAV9-mediated GBM immunotherapy.
