Arming AAV9 with a Single-Chain Fragment Variable Antibody Against PD-1 for Systemic Glioblastoma Therapy

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.