Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade

Christina A. Roemeling (), Jeet A. Patel, Savannah L. Carpenter, Oleg Yegorov, Changlin Yang, Alisha Bhatia, Bently P. Doonan, Rylynn Russell, Vrunda S. Trivedi, Kelena Klippel, Daniel H. Ryu, Adam Grippin, Hunter S. Futch, Yong Ran, Lan B. Hoang-Minh, Frances L. Weidert, Todd E. Golde and Duane A. Mitchell ()
Additional contact information
Christina A. Roemeling: University of Florida
Jeet A. Patel: University of Florida
Savannah L. Carpenter: University of Florida
Oleg Yegorov: University of Florida
Changlin Yang: University of Florida
Alisha Bhatia: University of Florida
Bently P. Doonan: University of Florida
Rylynn Russell: University of Florida
Vrunda S. Trivedi: University of Florida
Kelena Klippel: University of Florida
Daniel H. Ryu: Emory University School of Medicine
Adam Grippin: The University of Texas
Hunter S. Futch: Emory University School of Medicine
Yong Ran: Emory University School of Medicine
Lan B. Hoang-Minh: University of Florida
Frances L. Weidert: University of Florida
Todd E. Golde: Emory University School of Medicine
Duane A. Mitchell: University of Florida

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation. Herein, we develop a recombinant adeno-associated virus (AAV) gene therapy that enables focal and stable reconstitution of the tumor microenvironment with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for lymphocytes. By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by cytotoxic lymphocytes, sensitizing glioblastoma to anti-PD-1 immune checkpoint blockade in female preclinical tumor models. These effects are accompanied by immunologic signatures evocative of an inflamed tumor microenvironment. These findings support AAV gene therapy as an adjuvant for reconditioning glioblastoma immunogenicity given its safety profile, tropism, modularity, and off-the-shelf capability.

Date: 2024
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DOI: 10.1038/s41467-024-49989-1

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