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

Nature 2019 May; 569(7756)

Immunotherapy combined with PD-1 and CTLA-4 is effective for renal melanoma and non-small cell lung cancer.However, thiscomes at the cost of frequent, serious immune-related adverseevents, necessitating a reduction in the recommended dose ofipilimumab that is given to patients. Immune-related adverse events that result from therapy with checkpoint inhibitors are usually satisfactorily treated by discontinuing theuse of the therapeutic agents and beginning a course of steroids. However, after stopping the use of checkpoint inhibitors, the tumor could not be treated.

Colitis is among the most frequent and problematic immunemediated adverse events that are associated with dual checkpointinhibition.In order to minimize the immune events caused by this combination, the researchers used clinically available TNF inhibitors to treat mice with CTLA-4 and PD-1 immunotherapy to improve colitis. Their results demonstrate that prophylactic inhibition of TNF does not affect the anti-tumor activity of anti-PD-1 and anti-CTLA-4 combinations in mice that have established MC38 or B16-ovalbumin (OVA) derived tumours.In addition, this method also improve anti-tumor efficacy. They found that TNF blockade with anti-TNF or etanercept decreased apoptosis in T cell-receptor (TCR)-transgenic mouse CD8+ OT-I and Pmel-1 cells activated in culture with their respective cognate peptides in the presence of anti-PD-1 and anti-CTLA-4 monoclonal antibodies.

Next, the investigators analyzed gene expression due to checkpoint-induced colitis or who had been diagnosed with true ulcerative colitis. Notably,TNF is upregulated in the intestine of patients suffering fromcolitis after dual ipilimumab and nivolumab treatment. They also created a model in which Rag2-/-Il2rg-/-mice are adoptively transferred to human peripheral blood mononuclear cells, leading to further deterioration of graft-versus-host disease through ipilimumab and nivolumab.HT29 colon cancer cells were also transplanted subcutaneously into their constructed humanized mouse model, and it was observed that tumor progression was controlled to some extent by dual nivolumab and ipilimumab treatment.Moreover, xenograft-versus-host-induced hepatitis and colitis were markedly reduced in etanercept-treated mice.

TNF blockade is not new in the arena of cancer immunotherapy. Their results suggest that anti-TNF drugs may – at least in the gut and liver – improve the safety of combined ipilimumab and nivolumab immunotherapy, as well as equivalent or may improve their efficacy. If this hypothesis is correct, prophylactic TNF blockade may allow the dose of ipilimumab to safely increase the checkpoint blockade protocol in the immune combination, potentially enhancing their anti-tumor effects.