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Non-lytic viral immunotherapy induces long-term glioblastoma survival and tumor-specific immunity without eliciting an antiviral response.

Overview

Authors: Alexander F Haddad1, Atul Saha1,2, Sara A Collins1,3, Isabella Lovalvo1, Sabraj Gill1, Megan L Montoya1,4, Poojan Shukla1, Jinpyo Hong1,5, Elaina Wang1,6, Pavlina Chuntova1, Meeki Lad1, Robert Osorio1, Jia-Shu Chen1, Melissa Sathavipat1, Saket Jain1,4, Eric Chalif1,7, Noriyuki Kasahara1,8, Manish K Aghi1
ORCID iDs: Atul Saha, Isabella Lovalvo, Jinpyo Hong, Robert Osorio, Melissa Sathavipat, Noriyuki Kasahara, Manish K Aghi
  1. Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA USA
  2. Present Address: School of Medicine, University of California, San Diego, La Jolla, CA USA
  3. Present Address: 4D Molecular Therapeutics, Emeryville, CA USA
  4. Present Address: Genentech, South San Francisco, CA USA
  5. Present Address: Penn State College of Medicine, Hershey, PA USA
  6. Present Address: Department of Neurosurgery, Brown University, Providence, RI USA
  7. Present Address: Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
  8. Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA USA
Institutions: University of California, San Francisco (United States); University of California San Diego (United States); Genentech; Pennsylvania State University (United States); Brown University (United States); Brigham and Women's Hospital (United States); Harvard University (United States)
Journal: Nature communications, volume 17, issue 1, article 6613
Dates: received 13 February 2025; accepted 21 April 2026; published online 19 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-72746-5 · PMID 42156731 · PMCID PMC13381920 · OpenAlex W7161730088
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), other condition (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics
Keywords: CNS cancer, Cancer immunotherapy, Tumour immunology, Gene therapy
MeSH: Brain Neoplasms*, Glioblastoma*, Immunotherapy*, Retroviridae*, Animals, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Female, Humans, Immunologic Memory, Interleukin-15, Killer Cells, Natural, Mice, Mice, Inbred C57BL, Recombinant Fusion Proteins, Temozolomide (* major topic)
Topic: Virus-based gene therapy research (Genetics, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (5UE5NS070680-15, R01NS079697); NINDS NIH HHS (R01 NS079697, R01 NS123808, UE5 NS070680); NCI NIH HHS (P30 CA082103, R01 CA227136, R01 CA260443); U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) (R01CA260443); NIH HHS (S10 OD021818); U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA260443); U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (R01NS079697, 5UE5NS070680-15)
Citations: cited by 1 paper (Europe PMC); 78 references in the paper

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Code availability

No custom code was developed or utilized for this work. All analyses were performed using the software described in Methods.

Reproduced under the paper's license (CC BY), from the paper cited above.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

Data availability

Single-cell RNA sequencing data generated in this study have been deposited in the GEO repository (GSE278988 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE278988)). We also utilized publicly available data from the TCGA PanCancer Atlas (cBioPortal), CIBERSORTx, the McPAS TCR database, and previously published human GBM scRNA-seq data (GSE84465 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE84465))29,76. Source data are otherwise provided with this paper. GEO repository link for the scRNA sequencing data generated in this study: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE278988. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 18 authors, 4 keywords, 16 MeSH terms, 7 funders, 78 references.

Cite

This paper

Haddad, A. F., Saha, A., Collins, S. A., Lovalvo, I., Gill, S., Montoya, M. L., Shukla, P., Hong, J., Wang, E., Chuntova, P., Lad, M., Osorio, R., Chen, J.-S., Sathavipat, M., Jain, S., Chalif, E., Kasahara, N., & Aghi, M. K. (2026). Non-lytic viral immunotherapy induces long-term glioblastoma survival and tumor-specific immunity without eliciting an antiviral response. Nature communications, 17(1), 6613. https://doi.org/10.1038/s41467-026-72746-5

BibTeX

@article{haddad2026non,
author = {Haddad, Alexander F and Saha, Atul and Collins, Sara A and Lovalvo, Isabella and Gill, Sabraj and Montoya, Megan L and Shukla, Poojan and Hong, Jinpyo and Wang, Elaina and Chuntova, Pavlina and Lad, Meeki and Osorio, Robert and Chen, Jia-Shu and Sathavipat, Melissa and Jain, Saket and Chalif, Eric and Kasahara, Noriyuki and Aghi, Manish K},
title = {{Non-lytic viral immunotherapy induces long-term glioblastoma survival and tumor-specific immunity without eliciting an antiviral response}},
journal = {Nature communications},
year = {2026},
month = may,
volume = {17},
number = {1},
pages = {6613},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-72746-5},
url = {https://doi.org/10.1038/s41467-026-72746-5},
pmid = {42156731},
pmcid = {PMC13381920}
}

RIS

TY - JOUR
AU - Haddad, Alexander F
AU - Saha, Atul
AU - Collins, Sara A
AU - Lovalvo, Isabella
AU - Gill, Sabraj
AU - Montoya, Megan L
AU - Shukla, Poojan
AU - Hong, Jinpyo
AU - Wang, Elaina
AU - Chuntova, Pavlina
AU - Lad, Meeki
AU - Osorio, Robert
AU - Chen, Jia-Shu
AU - Sathavipat, Melissa
AU - Jain, Saket
AU - Chalif, Eric
AU - Kasahara, Noriyuki
AU - Aghi, Manish K
TI - Non-lytic viral immunotherapy induces long-term glioblastoma survival and tumor-specific immunity without eliciting an antiviral response
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/05/19
VL - 17
IS - 1
SP - 6613
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-72746-5
UR - https://doi.org/10.1038/s41467-026-72746-5
LA - en
ER -

CSL-JSON

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