Perez-Ruiz et al. show that administration of clinically available TNF inhibitors before or during dual anti-CTLA-4 and anti-PD-1 therapy prevents the emergence or exacerbation of immune-related adverse events (colitis) in mice, while maintaining or slightly enhancing CD8+ T cell infiltration and antitumor efficacy. TNF inhibition was associated with expansion of PD-1- T cells and attenuation of activation-induced cell death. The TNF pathway was active in patients who developed ICB-induced colitis, indicating that prophylactic TNF inhibition may improve the clinical safety of ICB and allow for more potent dosing.
Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer(1-3). 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 patients(4). 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.
Author Info: (1) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. Department of Oncology,
Author Info: (1) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. Department of Oncology, Hospital Costa del Sol, Marbella, Spain. Instituto de Investigacion Biomedica de Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, Malaga, Spain. (2) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (3) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (4) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (5) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. (6) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (7) Navarra Institute for Health Research (IDISNA), Pamplona, Spain. Department of Pathology, Clinica Universidad de Navarra, Pamplona, Spain. (8) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. (9) Navarra Institute for Health Research (IDISNA), Pamplona, Spain. Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. (10) Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. Department of Oncology, Hospital General Universitario Gregorio Maranon, Madrid, Spain. (11) Department of Oncology, Hospital Universitario Virgen de la Victoria, Malaga, Spain. (12) Instituto de Investigacion Biomedica de Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, Malaga, Spain. Laboratorio de Biologia Molecular del Cancer, Centro de Investigaciones Medico-Sanitarias (CIMES), Universidad de Malaga, Malaga, Spain. Department of Pathology, Faculty of Medicine, Universidad de Malaga, Malaga, Spain. (13) Instituto de Investigacion Biomedica de Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria, Malaga, Spain. Laboratorio de Biologia Molecular del Cancer, Centro de Investigaciones Medico-Sanitarias (CIMES), Universidad de Malaga, Malaga, Spain. (14) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. (15) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. (16) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. pberraondol@unav.es. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. pberraondol@unav.es. Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. pberraondol@unav.es. (17) Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain. imelero@unav.es. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. imelero@unav.es. Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. imelero@unav.es. Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. imelero@unav.es. Department of Immunology and Immunotherapy, Clinica Universidad de Navarra, Pamplona, Spain. imelero@unav.es.
