Non-lytic viral immunotherapy induces long-term glioblastoma survival and tumor-specific immunity without eliciting an antiviral response
- Alexander F. Haddad
- Atul Saha
- Sara A. Collins
- Isabella Lovalvo
- Sabraj Gill
- Megan L. Montoya
- Poojan Shukla
- Jinpyo Hong
- Elaina Wang
- Pavlina Chuntova
- Meeki Lad
- Robert Osorio
- Jia-Shu Chen
- Melissa Sathavipat
- Saket Jain
- Eric Chalif
- Noriyuki Kasahara
- Manish K. Aghi
2026-05-19
Glioblastoma is a lethal brain tumor that is resistant to conventional therapies. Here we present a non-lytic replicating retrovirus (RRV) that delivers an IL-15-receptor-linked fusion protein (RLI) superagonist directly into glioblastoma cells, creating localized immunotherapy biofactories. In orthotopic mouse models, RRV-RLI dramatically suppresses tumor growth, prolongs survival, and induces lasting remission with immunologic memory. Mechanistically, we observe increased CD8⁺ T cell and natural killer cell infiltration and activation, alongside elevated antigen presentation pathways. Combining RRV-RLI with temozolomide, which is standard-of-care chemotherapy for glioblastoma, enhances antitumor immunity. T cell receptor sequencing reveals a polyclonal repertoire of T cells, enhanced by combining RRV-RLI with temozolomide. Analysis of the T-cell repertoire suggests it to be directed against tumor rather than viral antigens, supporting the specificity and re-applicability of our approach. These findings illustrate that RRV-RLI reprograms glioblastoma into an immunostimulatory hub, offering a viral immunotherapy against glioblastoma and potentially other therapy-resistant solid tumors.