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dc.creatorPerez-Ruiz, E. (Elisabeth)-
dc.creatorMinute, L. (Luna)-
dc.creatorOtano, I. (Itziar)-
dc.creatorÁlvarez, M. (Maite)-
dc.creatorOchoa, M.C. (María Carmen)-
dc.creatorBelsue, V. (Virginia)-
dc.creatorAndrea, C.E. (Carlos Eduardo) de-
dc.creatorRodriguez-Ruiz, M. (María)-
dc.creatorPerez-Gracia, J.L. (Jose Luis)-
dc.creatorMarquez-Rodas, I. (Iván)-
dc.creatorLlacer, C. (Casilda)-
dc.creatorÁlvarez, M. (Martina)-
dc.creatorLuque, V. (Vanesa) de-
dc.creatorMolina, C. (Carmen)-
dc.creatorTeijeira, A. (Álvaro)-
dc.creatorBerraondo, P. (Pedro)-
dc.creatorMelero, I. (Ignacio)-
dc.identifier.citationPerez-Ruiz, E. (Elisabeth); Minute, L. (Luna); Otano, I. (Itziar); et al. "Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy". Nature. 569 (7756), 2019, 428 - 432es
dc.identifier.otherPMID: 31043740-
dc.description.abstractCombined 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.es_ES
dc.description.sponsorshipI.M. reports advisory roles with Roche-Genentech, BristolMyers Squibb, CYTOMX, Incyte, MedImmune, Tusk, F-Star, Genmab, Molecular Partners, Alligator, Bioncotech, MSD, Merck-Serono and Bayer, and research funding from Roche, BMS, Alligator and Bioncotech. P.B. reports advisory roles with Tusk and Moderna, research funding from Sanofi, Moderna and Bavarian Nordic and speaker honoraria from BMS, MSD, Novartis and AstraZeneca. I.M.-R. reports advisory roles with Roche-Genentech, Bristol-Myers Squibb, Incyte, Merck, Amgen, Pierre Fabre, Novartis, and Bioncotech. J.L.P.-G. reports advisory roles with Roche, MSD and BMS, travel support from Roche, BMS and MSD and research funding from Roche, BMS, MSD, Ipsen, Eisai, Incyte and Janssen. E.P.-R. reports speaker honoraria and travel support from BMS, MSD and Novartis.es_ES
dc.publisherSpringer Science and Business Media LLCes_ES
dc.subjectMaterias Investigacion::Ciencias de la Salud::Inmunologíaes_ES
dc.titleProphylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapyes_ES
dc.description.noteThe figures contain elements from Servier Medical Art (https://smart.servier.com/), licensed under Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)es_ES

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