Project Details

Description

Harnessing the immune system to fight cancer cells is now standard therapy for metastatic melanoma. Treatments such as ipilimumab, nivolumab and pembrolizumab, each of which targets an important immune regulatory protein, have revolutionized the treatment of melanoma, and now many patients have prolonged responses to therapy, greatly extending their lives. These new medications come with significant side effects. Ipilimumab, in particular, causes a variety of immune side effects, including inflammation in the colon (colitis). Untreated, ipilimumab-induced colitis can be life-threatening. Corticosteroids, which broadly inhibit the immune response, are currently given as standard therapy for ipilimumab-induced colitis and resolve the colitis in the majority of patients. About a third of patients with ipilimumab-induced colitis require treatment with an additional drug called infliximab. This treatment approach of giving steroids first, while generally effective, is not ideal. Steroids have broadly suppressive effects on the immune response, and it is possible that treatment of ipilimumab-induced colitis with steroids has a negative impact on the immune response to the cancer. We will perform a clinical trial (42 patients) to directly test whether it is better to give patients with ipilimumab-colitis steroids or infliximab. We will examine if one of these treatments is more effective in treating colitis, and which treatment is better for preserving the activity of the immune response against the cancer. We predict that infliximab will prove to be an effective medication for colitis and that it will also prove to be better in preserving the anti-cancer immune response. We will also study the effect of infliximab in comparison to steroids on the colon and the blood as a way of understanding the mechanism of action of this medication, potentially providing additional insights for treatment. We will examine which cell types are involved in the inflammation, as well as the inflammatory molecules that they are making, and the signals that are being sent. We will also use a technique to distinguish individual immune cells called T cells from each other, which is a way of figuring out if specific T cells are present in both the colon and the blood, and even potentially in the cancer. This project thereby aims to accomplish the following goals: 1) develop a better treatment for colitis that preserves the activity of the immune system against the cancer, 2) identify other molecules involved in causing colitis that could be targeted in patients who do not respond to current therapies, 3) identify cells in the blood involved in colitis which we can use to monitor the effect of treatment. The conclusions from this study will not only be relevant for the treatment of colitis, but for the treatment of other side effects caused by the powerful new immunotherapies.
StatusActive
Effective start/end date1/01/18 → …

Funding

  • Melanoma Research Alliance

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