Abstract
Glioblastoma is the most aggressive primary brain tumor with no cure, largely because of tumor heterogeneity and immunosuppressive tumor microenvironment. Chimeric antigen receptor (CAR)-T cell therapy is highly effective in blood cancers but exhibits limited efficacy in glioblastoma due to heterogeneous tumor antigen expression, antigen loss and poor persistence of tumor-targeting immune cells in glioblastoma. Here we show a multimodal immunotherapy strategy that integrates engineered immune cells with oncolytic viruses to overcome these barriers. We have developed bispecific CAR-T and CAR-NK cells in combination with oncolytic virus that delivers two tumor antigens to glioblastoma cells for effective CAR targeting. Moreover, oncolytic virus armed with membrane-bound interleukin-15 and interleukin-21 enhances immune cell expansion/persistence and cytotoxic activity. This combined approach improves anti-tumor efficacy in vitro and in vivo by limiting immune escape and enhancing anti-tumor immunity. Together, these findings establish a promising platform for multimodal immunotherapy targeting glioblastoma and other solid tumors.
Data availability
The RNA-seq dataset has been uploaded to GEO database with GEO# GSE310003 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi). Source data for all figures and Supplementary Figs. are provided within the paper.
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Acknowledgements
The authors would like to thank Louise and Herbert Horvitz for their generosity and forethought, Dr. Dario Campana from National University of Singapore for sharing the mbIL15 vector, and Dr. Carl June from University of Pennsylvania for sharing the EGFRvIII CAR vector. Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. BioRender has been used for preparing schematics.
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Conceptualization, Y.S. and J.L.; methodology, Y.S., J.L., S.C.; data acquisition and analysis, J.L., G.S.; investigation, J.L.; experimental support, G.S., S.C., Q.C., T.Z., Y.Q., and P.Y.; resources, X.W., Y.F., and M.V.M.; manuscript, Y.S. and J.L.
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S.C. is a consultant to Imugene Ltd. Y.F. is a paid scientific consultant for Medtronics, LivsMed, Imugene, Boston Scientific, Vergent, Eureka Therapeutics; receives royalties for inventions from Merck, XDemics, and Imugene Ltd; and owns the patent for CF33-Ovs licensed to Imugene Ltd. M.V.M. is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab and Luminary) and University of Pennsylvania (some licensed to Novartis). M.V.M. receives Grant/Research support from BMS, Kite Pharma, Sobi. M.V.M. holds Equity in Altido Therapeutics. M.V.M. is a compensated Consultant for A2Bio, Adaptimmune, Alexion, Astellas, AstraZeneca, BMS, Cabaletta Bio, In8bio, KSQ, and Lumicks.
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Li, J., Chaurasiya, S., Sun, G. et al. Developing a multimodal therapy for glioblastoma using oncolytic virus delivering CD19 and EGFRvIII antigens and bi-specific CARs . Nat Commun (2026). https://doi.org/10.1038/s41467-026-71021-x
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DOI: https://doi.org/10.1038/s41467-026-71021-x
