Combining JAK inhibitors with checkpoint inhibitors improves cancer immunotherapy response

Because not all cancer patients respond to a leading type of cancer immunotherapy drug, known as an immune checkpoint inhibitor, scientists explored whether adding janus kinase (JAK) inhibitors – drugs that treat chronic inflammation – could help. In two separate clinical studies, researchers found that adding JAK inhibitors did improve patients' responses to cancer checkpoint inhibitor immunotherapies.

"Aside from the exciting findings of the early phase trials reported by [both groups], they provide a great deal of data with complex analyses of immune responses," write Massimo Gadina and John O'Shea in a related Perspective. "It will be exciting to see how such sophisticated data might be used in the clinic and to inform research." Immune checkpoint inhibitors (ICIs) work by blocking checkpoint proteins on T cells that otherwise prevent the immune system from targeting and killing cancer cells. ICIs have substantially improved the treatment of some types of cancers. However, not all patients respond to these immunotherapies. And cancer patients often have chronic inflammation and immunosuppression, which can limit ICI treatment response.

In two independent clinical studies, researchers investigated whether using JAK inhibitors or jakinibs, which prevent inflammation from inside cells, could improve antitumor responses of anti-PD-1 ICI immunotherapy in cancer patients. Divij Mathew and colleagues conducted a phase II clinical trial to investigate the use of the JAK1 inhibitor itacitinib in combination with the anti-PD-1 ICI pembrolizumab as a first-line treatment for metastatic non-small cell lung cancer (NSCLC). Mathew et al. found that delayed administration of itacitinib following treatment of pembrolizumab improved the response of immunotherapy. According to the findings of the trial, which included 21 patients with treatment-naïve NSCLC, median progression-free survival was nearly 2 years, compared to the 6.5 to 10.3 months reported in other trials with only ICI. In a separate study, Jaroslav Zak and colleagues report results from a phase I/II clinical trial in patients with relapsing-refractory Hodgkin lymphoma who had previously received ICI and were unresponsive or showed mixed response. Zak et al. focused on the use of a combination of ruxolitinib, a JAK1 and JAK2 inhibitor, and the anti-PD-1 drug nivolumab. According to the findings, administration of ruxolitinib 8 days before the start of nivolumab therapy resulted in improved clinical efficacy in patients that had previously failed ICI immunotherapy. Among the 19 patients who participated, overall survival was 87% at 2 years compared to previous reports of 23.8% with ICI alone.

Science Senior Editor, Priscilla Kelly, commented: "These two clinical trials are notable because they pave the way for a new possible therapeutic strategy. The researchers find that in two different cancer types, combining Janus kinase (JAK) inhibitors with checkpoint inhibitor immunotherapy results in better clinical responses in patients with metastatic non-small cell lung cancer and those with relapsed or refractory Hodgkin lymphoma. In the study involving patients with metastatic non-small cell lung cancer, this combination therapy was delivered as a first-line treatment."

Source:
Journal reference:

Mathew, D., et al. (2024) Combined JAK inhibition and PD-1 immunotherapy for non–small cell lung cancer patients. Science. doi.org/10.1126/science.adf1329.

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