ArticleProceedings of the National Academy of Sciences of the United States of America2012
Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 7 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
78 citing papers in PubMed, 7 syntheses or guidelines pooled it, 119 citations in OpenAlex.
- Peripheral cytokine levels as novel predictors of survival in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.Frontiers in immunology · 2022Pooled it
- What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment.International journal of molecular sciences · 2021Pooled it
- What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1.International journal of molecular sciences · 2021Pooled it
- What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models).International journal of molecular sciences · 2021Pooled it
- Pooled it
- Pooled it
- The prognostic value of cytotoxic T-lymphocyte antigen 4 in cancers: a systematic review and meta-analysis.Scientific reports · 2017Pooled it
- Solid tumour CAR-T cells engineered with fusion proteins targeting PD-L1 for localized IL-12 delivery.Nature biomedical engineering · 2026Article
- Advances in IL-15-Based Cancer Immunotherapy and Divergent Immunological Effects of IL-2 and IL-15 Signaling via the Shared IL-2Rβγ Receptor.Frontiers in immunology · 2026Review
- Phase 1 study evaluating the safety, preliminary efficacy, and pharmacodynamics of recombinant interleukin-15 in combination with nivolumab and ipilimumab in patients with refractory cancers.Journal for immunotherapy of cancer · 2025Article
- Probiotic-mediated tumor microenvironment reprogramming with protease-sensitive interleukin-15 and photothermal therapy.Cell reports. Medicine · 2025Article
- Off-the-shelf invariant NKT cells expressing anti-PSCA CAR and IL-15 promote pancreatic cancer regression in mice.The Journal of clinical investigation · 2025Article
- Soluble PD-L1: From Immune Evasion to Cancer Therapy.Life (Basel, Switzerland) · 2025Review
- Interim report on engineered NK cell trial in lung cancer refractory to immune checkpoint inhibitors.JCI insight · 2025Article
- A landscape of checkpoint blockade resistance in cancer: underlying mechanisms and current strategies to overcome resistance.Cancer biology & therapy · 2024Review
- Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia.International journal of molecular sciences · 2024Review
- Preclinical Evaluation of Off-The-Shelf PD-L1+ Human Natural Killer Cells Secreting IL15 to Treat Non-Small Cell Lung Cancer.Cancer immunology research · 2024Article
- Prostate cancer therapy using immune checkpoint molecules to target recombinant dendritic cells.Investigative and clinical urology · 2024Article
- Extracellular vesicles as tools and targets in therapy for diseases.Signal transduction and targeted therapy · 2024Review
- Leveraging long-acting IL-15 agonists for intratumoral delivery and enhanced antimetastatic activity.Frontiers in immunology · 2024Article
18 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
IL-15 has potential as an immunotherapeutic agent for cancer treatment because of its ability to effectively stimulate CD8 T cell, natural killer T cell, and natural killer cell immunity. However, its effectiveness may be limited by negative immunological checkpoints that attenuate immune responses. Recently a clinical trial of IL-15 in cancer immunotherapy was initiated. Finding strategies to conquer negative regulators and enhance efficacy of IL-15 is critical and meaningful for such clinical trials. In a preclinical study, we evaluated IL-15 combined with antibodies to block negative immune regulator cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in an established murine transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 prostate tumor model. IL-15 treatment resulted in a significant prolongation of survival in tumor-bearing animals. Coadministration of anti-PD-L1 or anti-CTLA-4 singly with IL-15 did not improve animal survival over that of IL-15 alone. However, simultaneous administration of IL-15 with anti-CTLA-4 and anti-PD-L1 was associated with increased numbers of tumor antigen-specific tetramer-positive CD8 T cells, increased CD8 T-cell tumor lytic activity, augmented antigen-specific IFN-γ release, decreased rates of tumor growth, and improved animal survival compared with IL-15 alone. Furthermore, triple combination therapy was associated with inhibition of suppressive functions of CD4(+)CD25(+) regulatory T cells and CD8(+)CD122(+) regulatory T cells. Thus, simultaneous blockade of CTLA-4 and PD-L1 protected CD4 and/or CD8 T-cell activity from these regulatory T cells. Combining the immune stimulatory properties of IL-15 with simultaneous removal of two critical immune inhibitory checkpoints, we showed enhancement of immune responses, leading to increased antitumor activity.
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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.