The combination of anti-PD-1 and anti-CTLA-4 antibody-mediated immunotherapy is remarkably effective against melanoma, renal cell carcinoma, and non-small-cell lung cancer. However, this comes at the cost of frequent, serious immune-related adverse events. Colitis is among the most frequent and problematic of the immune-mediated adverse events that are associated with dual checkpoint inhibition.

Currently, these immune-related adverse events are treated by discontinuing anti-PD-1 and anti-CTLA-4 treatment and beginning a course of steroids. In serious cases, patients are given an anti-TNF antibody to reduce inflammation.

To identify the extent to which TNF inhibitors can be used to mitigate the side effects of combined immunotherapy Dr. Ignacio Melero’s group at Cima and Clinica Universidad de Navarra used mouse models of colitis and cancer. The authors first established that prophylactic treatment with anti-TNF antibodies ameliorates the exacerbation of colitis caused by anti-PD-1 and anti-CTLA-4. The authors then studied whether prophylactic TNF blockade affects the anti-tumor activity of anti-PD-1 and anti-CTLA-4 combination treatment in mice with established tumors. The authors discovered that prophylactic TNF blockade did not hinder but remarkably it enhanced the anti-tumor activity of combined anti-PD-1 and anti-CTLA-4 immunotherapy.

To address the clinical applicability of the mouse data, the authors created a humanized mouse model in which human PBMCs were infused into mice lacking functional lymphocytes. This causes the mice to develop a colitis-like condition. As expected, treating these mice with the anti-human PD-1 and CTLA-4 drugs ipilimumab and nivolumab exacerbated the inflammation. Prophylactic treatment of these mice with the anti-human TNF drug etanercept reduced inflammation in the large intestine and markedly reduced colitis symptoms.

This study indicates that prophylactic anti-TNF treatment may improve the safety of combined ipilimumab and nivolumab immunotherapy, as well as equaling or perhaps enhancing its efficacy. If this hypothesis is correct, prophylactic TNF blockade might allow doses of ipilimumab to be safely increased in combined immune checkpoint blockade regimens, thereby potentially strengthening their anti-tumor effects.

The authors used Bio X Cell’s anti-mouse PD-1 (clone RMP1-14)anti-mouse CTLA-4 (clone 9D9) and anti-mouse TNFα (clone XT3.11) antibodies in preclinical mouse models.

See the complete article in Nature:


Perez-Ruiz, E., Minute, L., Otano, I. et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature 569, 428–432 (2019).