International Business Department           Liu Bojia           January 16, 2023

  Tumour immunotherapy, represented by immune checkpoint inhibitors, has been widely used in the treatment of a range of cancers by activating the body's immune system to exert an anti-tumour effect, to the benefit of many patients around the world. However, like all drugs, immune checkpoint inhibitor drugs are associated with adverse effects. Immune-related adverse events (irAE) are some of the more serious and prominent adverse effects of this type of anti-tumour therapy.

  Colitis is a common immune-related adverse event in patients receiving CTLA-4 inhibitors (monoclonal antibodies targeting the checkpoint protein CTLA-4). Colitis is characterised by inflammation of the lining of the colon, which can cause severe gastrointestinal discomfort and in some patients interrupt treatment.

  In animal experiments, however, lab-raised mice receiving immune checkpoint inhibitors are highly resistant to intestinal inflammation and rarely develop intense colitis, making it difficult in the past for researchers to understand the mechanism of this adverse effect.

  Happily, in a newly published paper in the leading academic journal Science, scientists have finally identified the crux of this severe adverse reaction and provided a corresponding solution, which is expected to lead to the development of next-generation CTLA-4 inhibitors with reduced inflammatory toxicity, i.e., capable of stimulating anti-tumour immune responses while overcoming and preventing intestinal immune-related adverse events.

  In the new study, a team of researchers from the University of Michigan, USA, constructed a mouse model that differs from traditional husbandry in that these mice, whose gut flora more closely resembles that of mice captured in the wild, develop pronounced colitis after treatment with anti-CTLA-4 antibodies and examination of inflammatory tissues showed several hallmarks of the adverse effects of colitis in clinically tumour-immune patients.

  With these experimental mice, which can mimic human patients, the researchers first established that intestinal immune-related adverse events are closely linked to the composition of the intestinal flora, and then went further to find the mechanisms behind intestinal inflammation.

  According to the paper, colitis arises as a result of unrestricted activation of interferon-producing T cells, whereas a population of regulatory T cells that inhibit T cell activation is depleted by binding to the Fc structural domain of the anti-CTLA-4 monoclonal antibody.

  Based on the phenomenon observed in the mice, they also re-analysed data from past patients treated with immune checkpoint inhibitor antibodies to confirm the role of regulatory T cells in inducing the development of colitis.

  The researchers then came up with a countermeasure: by deleting the Fc structural domain of the anti-CTLA-4 antibody, wouldn't it be possible to preserve the anti-tumour response while avoiding the induction of colitis? In fact, pharmaceutical companies have already developed such anti-CTLA-4 nanobodies with the Fc domain missing, and the results of the mouse experiments tentatively confirmed their suspicions.

  The study authors conclude that this work shows for the first time that gut flora is critical for the development of colitis induced by immune checkpoint inhibitor therapy. They plan to further identify the mechanisms of intestinal immune-related adverse events and to benefit patients at an early stage through collaboration with the clinic.