Journal Article

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

Llacer, Casilda, Berraondo, Pedro, Otano, Itziar, Perez-Gracia, Jose Luis, Melero, Ignacio, Minute, Luna, Perez-Ruiz, Elisabeth, Molina, Carmen, de Andrea, Carlos, Teijeira, Alvaro, de Luque, Vanesa, Belsue, Virginia, Rodriguez-Ruiz, Maria Esperanza, Alvarez, Maite, Alvarez, Martina, Marquez-Rodas, Ivan, Ochoa, Maria Carmen

2019

Overview

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 , 2 – 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. In mice, prophylactic administration of TNF inhibitors mitigates some of the immune-related adverse effects of immune checkpoint blockade treatment, and also improves to some extent the anti-tumour effect of this immunotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/2 / 13/21 / 13/31 / 13/51 / 14 / 38 / 59 / 631/250/251 / 631/67/580 / 64/60 / 82/1 / Animals / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - pharmacology / Antibodies, Monoclonal - therapeutic use / Anticancer properties / Cancer / Cancer immunotherapy / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Colitis / Colitis - drug therapy / Colon / Colon cancer / Colonic Neoplasms - drug therapy / Colonic Neoplasms - immunology / Colorectal cancer / Combined modality therapy / Complications and side effects / CTLA-4 Antigen - antagonists & inhibitors / CTLA-4 Antigen - immunology / CTLA-4 protein / Dextran Sulfate - pharmacology / Disease / Dosage and administration / Drug therapy / Effectiveness / Experiments / Female / Graft vs Host Disease / Graft-versus-host reaction / Hepatitis / Hepatitis - drug therapy / Humanities and Social Sciences / Humans / Immune checkpoint / Immune checkpoint inhibitors / Immunoglobulins / Immunotherapy / Immunotherapy - adverse effects / Independent sample / Inflammatory bowel disease / Inhibitors / Intestine / Ipilimumab - adverse effects / Kidney cancer / Letter / Leukocytes (mononuclear) / Lung cancer / Lung carcinoma / Lung diseases / Lymphatic system / Lymphocytes / Male / Melanoma / Methods / Mice / Mice, Inbred C57BL / Monoclonal antibodies / multidisciplinary / Nivolumab - adverse effects / Non-small cell lung carcinoma / Ovarian cancer / Patient outcomes / PD-1 protein / Peptides / Peripheral blood mononuclear cells / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - immunology / Prophylaxis / RAG2 protein / Renal cell carcinoma / Science / Science (multidisciplinary) / Sodium / T-Lymphocytes - drug effects / T-Lymphocytes - immunology / Targeted cancer therapy / TNF inhibitors / Toxicity / Tumor necrosis factor / Tumor necrosis factor inhibitors / Tumor Necrosis Factor Inhibitors - pharmacology / Tumor Necrosis Factor Inhibitors - therapeutic use / Tumor Necrosis Factor-alpha - antagonists & inhibitors / Tumor necrosis factor-TNF / Tumors / Ultrasonic imaging / Variance analysis / Xenograft Model Antitumor Assays / Xenografts