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Nature. 2019 May;569(7756):428-432. doi: 10.1038/s41586-019-1162-y. Epub 2019 May 1.

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

Author information

1
Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.
2
Navarra Institute for Health Research (IDISNA), Pamplona, Spain.
3
Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
4
Department of Oncology, Hospital Costa del Sol, Marbella, Spain.
5
Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, Málaga, Spain.
6
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
7
Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain.
8
Department of Oncology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.
9
Department of Oncology, Hospital Universitario Virgen de la Victoria, Málaga, Spain.
10
Laboratorio de Biología Molecular del Cáncer, Centro de Investigaciones Médico-Sanitarias (CIMES), Universidad de Málaga, Málaga, Spain.
11
Department of Pathology, Faculty of Medicine, Universidad de Málaga, Málaga, Spain.
12
Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. pberraondol@unav.es.
13
Navarra Institute for Health Research (IDISNA), Pamplona, Spain. pberraondol@unav.es.
14
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. pberraondol@unav.es.
15
Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. imelero@unav.es.
16
Navarra Institute for Health Research (IDISNA), Pamplona, Spain. imelero@unav.es.
17
Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain. imelero@unav.es.
18
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. imelero@unav.es.
19
Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain. imelero@unav.es.

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.

PMID:
31043740
DOI:
10.1038/s41586-019-1162-y

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