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Cited by 480Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy

Open access
Perez-Ruiz, Elisabeth, Minute, Luna, Otano, Itziar, Alvarez, Maite, Ochoa, Maria Carmen, Belsue, Virginia, de Andrea, Carlos, Rodriguez-Ruiz, Maria Esperanza +9 more·2019·Nature
DOI 10.1038/s41586-019-1162-y
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Abstract

Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer1–3. However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of ipilimumab that is given to patients4. In mice, co-treatment with surrogate anti-PD-1 and anti-CTLA-4 monoclonal antibodies is effective in transplantable cancer models, but also exacerbates autoimmune colitis. Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2−/−Il2rg−/− mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy. In mice, prophylactic administration of TNF inhibitors mitigates some of the immune-related adverse effects of immune checkpoint blockade treatment, and also improves to some extent the anti-tumour effect of this immunotherapy.

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Crossref · 10.1038/s41586-019-1162-y

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  • Other published reports showed evidence in mouse models that anti-TNF-a enhances the antitumor activity of combined anti-PD-1 and anti-CTLA-4 immunotherapy, reinforces both CD8 T-cell-dependent immunity and anti-PD-1 therapy, by preventing anti-PD-1-induced cell death of tumor infiltrating lymphocytes as well as PD-L1 and Tim-3 expression.

    “Contrarily, other published reports showed evidence in mouse models that anti-TNF-a enhances the antitumor activity of combined anti-PD-1 and anti-CTLA-4 immunotherapy, 61 reinforces both CD8 T-cell-dependent immunity and anti-PD-1 therapy, by preventing anti-PD-1-induced cell death of tumor infiltrating lymphocytes as well as PD-L1 and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3)”

    From Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy (2020) · cites this paper as [61]

  • A preclinical study found that prophylactic TNF blockade could dissociate the efficacy and toxicity of α-CTLA-4 plus α-PD-1/PD-L1 therapy.

    “A preclinical study found that prophylactic TNF blockade could dissociate the efficacy and toxicity of α-CTLA-4 plus α-PD-1/PD-L1 therapy [155].”

    From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [155]

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Authors
Perez-Ruiz, E., Minute, L., Otano, I., Alvarez, M., Ochoa, M. C., Belsue, V., de Andrea, C., Rodriguez-Ruiz, M. E., Perez-Gracia, J. L., Marquez-Rodas, I., Llacer, C., Alvarez, M., de Luque, V., Molina, C., Teijeira, A., Berraondo, P., & Melero, I.
Affiliations
  • Navarre Institute of Health Research (ES)
  • Clinica Universidad de Navarra (ES)
Corresponding author
  • Berraondo, Pedro
  • Melero, Ignacio
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-05-01
Volume
569
Issue
7756
Pages
428-432
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1162-y
OpenAlex
W2943218134
Cited by
480
References
33
Citations by year
2026: 42 · 2025: 49 · 2024: 77 · 2023: 67 · 2022: 65 · 2021: 74 · 2020: 82 · 2019: 22
FWCI
25.39
Type
journal article
Language
en
Update notices
correction (2025-10-01)
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Deposito Adademico Digital Universidad De Navarra (University of Navarra) (submittedVersion, cc-by)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
anti-TNF therapy, immune checkpoint blockade, CTLA-4, PD-1, nivolumab, ipilimumab, immune-related adverse events, colitis, graft-versus-host disease, TNF-α, antitumour efficacy, melanoma, renal cell carcinoma, non-small cell lung cancer, tumor xenografts, hepatitis
MeSH terms
Ipilimumab, Nivolumab, Tumor Necrosis Factor Inhibitors, Animals, Antibodies, Monoclonal, Colitis, Colonic Neoplasms, Female, Graft vs Host Disease, Hepatitis, Humans, Immunotherapy, Male, Mice, Inbred C57BL, T-Lymphocytes, Tumor Necrosis Factor-alpha, Dextran Sulfate, CD8-Positive T-Lymphocytes, Xenograft Model Antitumor Assays, Mice, CTLA-4 Antigen, Programmed Cell Death 1 Receptor

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