Armed Oncolytic Adenovirus-Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells...

Area of Science:

• Oncolytic virotherapy
• Immunotherapy
• Cancer research

Background:

• Chimeric antigen receptor (CAR) T cells can be inhibited by PD-L1 checkpoint signals on tumor cells.
• Oncolytic adenoviruses (Onc.Ad) can induce local immune responses.
• Developing strategies to enhance CAR T-cell efficacy against solid tumors is crucial.

Purpose of the Study:

• To evaluate a helper-dependent adenovirus (HDAd) expressing a PD-L1 blocking mini-antibody (HD*PDL1*) for enhancing CAR T-cell therapy.
• To assess the efficacy of coadministering HD*PDL1* with CAR T cells in human tumor xenograft models.
• To investigate the benefits of locally produced PD-L1 mini-body compared to systemic administration.

Main Methods:

• Co-administration of an oncolytic adenovirus (Onc.Ad) engineered to express a PD-L1 blocking mini-body (HD*PDL1*) with HER2.CAR T cells in human tumor xenograft models.
• Evaluation of oncolytic effects and local PD-L1 mini-body production at the tumor site.
• Comparison of combination therapy with CAR T cells alone, Onc.Ad alone, and systemic anti-PD-L1 antibody treatment.

Main Results:

• Coadministration of HD*PDL1* and CAR T cells (CAd-VEC*PDL1*) demonstrated enhanced antitumor activity compared to monotherapies.
• Local production of PD-L1 mini-body by CAd-VEC*PDL1* was superior to systemic anti-PD-L1 IgG administration in combination with CAR T cells.
• The combination therapy effectively controlled tumor growth in HER2+ prostate cancer xenograft models.

Conclusions:

• Local production of PD-L1 mini-body via engineered oncolytic adenovirus is a superior strategy to enhance CAR T-cell therapy.
• This approach overcomes PD-L1-mediated inhibition and improves CAR T-cell functionality against solid tumors.
• The combination of tumor-directed CAR T cells and locally produced PD-L1 blockade offers a promising therapeutic strategy for solid tumor treatment.