A Dendritic Cell-Targeted Adenoviral Vector Facilitates Adaptive Immune Response Against Human Glioma Antigen (CMV-IE) and Prolongs Survival in a Human Glioma Tumor Model.

in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics by Julius W Kim, J Robert Kane, Wojciech K Panek, Jacob S Young, Aida Rashidi, Dou Yu, Deepak Kanojia, Tanwir Hasan, Jason Miska, Miguel A Gómez-Lim, Ilya V Ulasov, Irina V Balyasnikova, Atique U Ahmed, Derek A Wainwright, Maciej S Lesniak

TLDR

  • Researchers develop a DC-specific adenoviral vector for targeted antigen presentation and demonstrate its efficacy in prolonging survival and inducing complete rejection of cancerous cells in a murine glioma model.

Abstract

Antitumor immunotherapeutic strategies represent an especially promising set of approaches with rapid translational potential considering the dismal clinical context of high-grade gliomas. Dendritic cells (DCs) are the body's most professional antigen-presenting cells, able to recruit and activate T cells to stimulate an adaptive immune response. In this regard, specific loading of tumor-specific antigen onto dendritic cells potentially represents one of the most advanced strategies to achieve effective antitumor immunization. In this study, we developed a DC-specific adenoviral (Ad) vector, named Ad5scFvDEC205FF, targeting the DC surface receptor, DEC205. In vitro analysis shows that 60% of DCs was infected by this vector while the infectivity of other control adenoviral vectors was less than 10%, demonstrating superior infectivity on DCs. Moreover, an average of 14% of DCs were infected by Ad5scFvDEC205FF-GFP, while less than 3% of non-DCs were infected following in vivo administration, demonstrating highly selective in vivo DC infection. Importantly, vaccination with this vehicle expressing human glioma-specific antigen, Ad5scFvDEC205FF-CMV-IE, shows a prolonged survival benefit in GL261-implanted murine glioma models (p < 0.0007). Furthermore, when rechallenged, cancerous cells were completely rejected. In conclusion, our novel, viral-mediated, DC-based immunization approach has the significant therapeutic potential for patients with high-grade gliomas.

Overview

  • The study focuses on developing an antitumor immunotherapeutic strategy using dendritic cells (DCs) as antigen-presenting cells to recruit and activate T cells against high-grade gliomas.
  • The researchers developed a DC-specific adenoviral vector, Ad5scFvDEC205FF, targeting the DC surface receptor, DEC205, for selective infection and antigen presentation.
  • The primary objective of the study is to evaluate the therapeutic potential of this viral-mediated, DC-based immunization approach for patients with high-grade gliomas.

Comparative Analysis & Findings

  • In vitro analysis shows that Ad5scFvDEC205FF demonstrated superior infectivity on DCs (60%) compared to control adenoviral vectors (<10% infectivity).
  • In vivo administration of Ad5scFvDEC205FF-GFP resulted in selective infection of DCs (14%) and minimal infection of non-DCs (<3%).
  • Vaccination with Ad5scFvDEC205FF-CMV-IE, expressing human glioma-specific antigen, showed a prolonged survival benefit in GL261-implanted murine glioma models (p < 0.0007), with complete rejection of cancerous cells upon rechallenge.

Implications and Future Directions

  • The study highlights the significant therapeutic potential of this novel, viral-mediated, DC-based immunization approach for patients with high-grade gliomas.
  • Future research directions may include investigating the effectiveness of this approach in other cancer types and refining the vector design for improved antigen presentation and immune responses.
  • The study also suggests potential applications for this technology in other immune-oncology therapeutics, such as combination immunotherapy strategies and personalized neoantigen-based vaccines.
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