ArticleOncoimmunology
Order of administration of combination cytokine therapies can decouple toxicity from efficacy in syngeneic mouse tumor models.
Article in Oncoimmunology. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- A Phase Ib Study of Atezolizumab with Radium-223 Dichloride in Men with Metastatic Castration-Resistant Prostate Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Trial
- Engineering drug-responsive replication machinery for precise control of self-amplifying RNA.Nature biomedical engineering · 2026Article
- Engineering gene expression dynamics via self-amplifying RNA with drug-responsive non-structural proteins.bioRxiv : the preprint server for biology · 2025Article
- Enhancing immunotherapy with tumour-responsive nanomaterials.Nature reviews. Clinical oncology · 2025Review
- Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Intratumorally anchored cytokine therapy.Expert opinion on drug delivery · 2022Article
- 89Zr-ImmunoPET Shows Therapeutic Efficacy of Anti-CD20-IFNα Fusion Protein in a Murine B-cell Lymphoma Model.Molecular cancer therapeutics · 2022Article
- Translational Applications of Hydrogels.Chemical reviews · 2021Review
- Engineering Strategies for Immunomodulatory Cytokine Therapies - Challenges and Clinical Progress.Advanced therapeutics · 2021Article
- Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial.Breast cancer research : BCR · 2020Article
- Improving cancer immunotherapy through nanotechnology.Nature reviews. Cancer · 2019Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
In combination cancer immunotherapies, consideration should be given to designing treatment schedules that harmonize with the immune system's natural timing. An efficacious temporally programmed combination therapy of extended half-life interleukin 2 (eIL2), tumor targeting antibody, and interferon (IFN) α was recently reported; however, tumor-ablative efficacy was associated with significant toxicity. In the current work, altering the order and timing of the three agents is shown to decouple toxicity from efficacy. Delaying the administration of eIL2 to be concurrent with or after IFNα eliminates toxicity without affecting efficacy in multiple syngeneic tumor models and mouse strains. The toxicity resulting from eIL2 administration before IFNα is dependent on multiple systemic inflammatory cytokines including IL6, IL10, IFNγ, and tumor necrosis factor α. Natural killer (NK) cells are the main cellular contributor to toxicity, but are not essential for tumor control in this system. When pre-conditioned with eIL2, splenic NK cells became hyper-activated and upregulate IFNα signaling proteins that cause an excessive, toxic response to subsequent IFNα exposure. This work illustrates an example where accounting for the temporal dynamics of the immune system in combination therapy treatment schedule can favorably decouple efficacy and toxicity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.