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

Elisabeth Perez-Ruiz, Luna Minute, Itziar Otano, Maite Alvarez, Maria Carmen Ochoa, Virginia Belsue, Carlos de Andrea, Maria Esperanza Rodriguez-Ruiz, Jose Luis Perez-Gracia, Ivan Marquez-Rodas, Casilda Llacer, Martina Alvarez, Vanesa de Luque, Carmen Molina, Alvaro Teijeira, Pedro Berraondo () and Ignacio Melero ()
Additional contact information
Elisabeth Perez-Ruiz: Cima Universidad de Navarra
Luna Minute: Cima Universidad de Navarra
Itziar Otano: Cima Universidad de Navarra
Maite Alvarez: Cima Universidad de Navarra
Maria Carmen Ochoa: Cima Universidad de Navarra
Virginia Belsue: Cima Universidad de Navarra
Carlos de Andrea: Navarra Institute for Health Research (IDISNA)
Maria Esperanza Rodriguez-Ruiz: Cima Universidad de Navarra
Jose Luis Perez-Gracia: Navarra Institute for Health Research (IDISNA)
Ivan Marquez-Rodas: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Casilda Llacer: Hospital Universitario Virgen de la Victoria
Martina Alvarez: Hospitales Universitarios Regional y Virgen de la Victoria
Vanesa de Luque: Hospitales Universitarios Regional y Virgen de la Victoria
Carmen Molina: Cima Universidad de Navarra
Alvaro Teijeira: Cima Universidad de Navarra
Pedro Berraondo: Cima Universidad de Navarra
Ignacio Melero: Cima Universidad de Navarra

Nature, 2019, vol. 569, issue 7756, 428-432

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1162-y

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