ArticleJournal for immunotherapy of cancer2021
Differential combination immunotherapy requirements for inflamed (warm) tumors versus T cell excluded (cool) tumors: engage, expand, enable, and evolve.
Article in Journal for immunotherapy of cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
What it found
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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
40 citing papers in PubMed, 52 citations in OpenAlex.
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- Nimotuzumab Concurrent with Gemcitabine as First-Line Treatment of Locally Advanced or Metastatic Pancreatic Adenocarcinoma.BioMed research international · 2023Trial
- Tumor sialylation regulates G-CSF stability and promotes neutrophil-mediated immunosuppression in breast cancer.Nature communications · 2026Article
- Effect of clinically relevant iron oxide nanoparticles on macrophage polarization, tumor growth and tumor microenvironment modulation.Journal of controlled release : official journal of the Controlled Release Society · 2026Article
- AND logic nanoparticle for precision immunotherapy of metastatic cancers.Nature nanotechnology · 2026Article
- Divergent role of CD8 T cells with distinct metabolic phenotypes during curative radio-immunotherapy in hot versus cold tumors.bioRxiv : the preprint server for biology · 2026Article
- TIME for Endometrial Cancer: Advancements and Challenges in Therapeutic Targets for the Endometrial Cancer Tumor Immune Microenvironment.Cancer immunology research · 2025Review
- Local delivery of IL-15 and anti-PD-L1 nanobody by in vitro-transcribed circILNb elicits superior antitumor immunity in cold tumors.Cell reports. Medicine · 2025Article
- Probiotic-mediated tumor microenvironment reprogramming with protease-sensitive interleukin-15 and photothermal therapy.Cell reports. Medicine · 2025Article
- Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models.Nature communications · 2025Article
- The impact of diet-induced obesity on 5 fluorouracil-induced tumor and liver immune cell cytotoxicity.American journal of physiology. Cell physiology · 2025Article
- A landscape of checkpoint blockade resistance in cancer: underlying mechanisms and current strategies to overcome resistance.Cancer biology & therapy · 2024Review
- Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer.Molecular cancer · 2024Review
- Multifunctional Nanovaccine Sensitizes Breast Cancer to Immune Checkpoint Therapy.Advanced functional materials · 2024Article
- Histoplasty Modification of the Tumor Microenvironment in a Murine Preclinical Model of Breast Cancer.Journal of vascular and interventional radiology : JVIR · 2024Article
- Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer.Molecular oncology · 2023Article
- Dose-Specific Intratumoral GM-CSF Modulates Breast Tumor Oxygenation and Antitumor Immunity.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential.Experimental & molecular medicine · 2023Review
- Mathematical modeling indicates that regulatory inhibition of CD8+ T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load.PLoS computational biology · 2023Article
- Exploiting docetaxel-induced tumor cell necrosis with tumor targeted delivery of IL-12.Cancer immunology, immunotherapy : CII · 2023Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
backgroundDifferent types of tumors have varying susceptibility to immunotherapy and hence require different treatment strategies; these cover a spectrum ranging from 'hot' tumors or those with high mutational burden and immune infiltrates that are more amenable to targeting to 'cold' tumors that are more difficult to treat due to the fewer targetable mutations and checkpoint markers. We hypothesized that an effective anti-tumor response requires multiple agents that would (1)
methodsA hexatherapy combination was designed and administered to MC38-CEA (warm) and 4T1 (cool) murine tumor models. The hexatherapy regimen was composed of adenovirus-based vaccine and IL-15 (interleukin-15) superagonist (N-803) to engage the immune response; anti-OX40 and anti-4-1BB to expand effector cells; anti-PD-L1 (anti-programmed death-ligand 1) to enable anti-tumor activity; and docetaxel to promote antigen spread. Primary and metastatic tumor growth inhibition were measured. The generation of anti-tumor immune effector cells was analyzed using flow cytometry, ELISpot (enzyme-linked immunospot), and RNA analysis.
resultsThe MC38-CEA and 4T1 tumor models have differential sensitivities to the combination treatments. In the 'warm' MC38-CEA, combinations with two to five agents resulted in moderate therapeutic benefit while the hexatherapy regimen outperformed all these combinations. On the other hand, the hexatherapy regimen was required in order to decrease the primary and metastatic tumor burden in the 'cool' 4T1 model. In both models, the hexatherapy regimen promoted CD4
conclusionThe hexatherapy regimen is a strategic combination of immuno-oncology agents that can engage, expand, enable, and evolve the immune response and can provide therapeutic benefits in both MC38-CEA (warm) and 4T1 (cool) tumor models.
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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.