RT Journal Article
T1 Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.
A1 Perez-Ruiz, Elisabeth
A1 Minute, Luna
A1 Otano, Itziar
A1 Alvarez, Maite
A1 Ochoa, Maria Carmen
A1 Belsue, Virginia
A1 de-Andrea, Carlos
A1 Rodriguez-Ruiz, Maria Esperanza
A1 Perez-Gracia, Jose Luis
A1 Marquez-Rodas, Ivan
A1 Llacer, Casilda
A1 Alvarez, Martina
A1 de-Luque, Vanesa
A1 Molina, Carmen
A1 Teijeira, Alvaro
A1 Berraondo, Pedro
A1 Melero, Ignacio
K1 Antibodies, Monoclonal
K1 CD8-Positive T-Lymphocytes
K1 CTLA-4 Antigen
K1 Colitis
K1 Colonic Neoplasms
AB 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.
PB Nature Publishing Group
YR 2019
FD 2019-05-01
LK http://hdl.handle.net/10668/13899
UL http://hdl.handle.net/10668/13899
LA en
NO Perez-Ruiz E, Minute L, Otano I, Alvarez M, Ochoa MC, Belsue V, et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature. 2019 May;569(7756):428-432
NO This work was supported by the International Immuno-Oncology Network (II-ON) from Bristol-Myers Squibb; a Worldwide Cancer Research Grant (15-1146); the Asociación Española Contra el Cancer (AECC) Foundation under grant GCB15152947MELE; the Instituto Carlos III (under grants PI14/01686,PI13/00207 and PI16/00668) co-financed with FEDER funds; and theEuropean Union's Horizon 2020 Program (grant agreement no. 635122PROCROP). P.B. is supported by a Miguel Servet II (CPII15/00004) contractfrom Instituto de Salud Carlos III; E.P.-R is supported by the Carmen Lavignetraining program of the Asociación Española contra el Cancer and by Consejeriade Salud de la Junta de Andalucía; and A.T. has received financial supportthrough la Caixa Banking Foundation (LCF/BQ/LR18/11640014).
DS RISalud
RD Jul 1, 2025