JAK inhibition enhances immunotherapy in Hodgkin lymphoma

Blood cancers

By Michael Woodhead

30 Jun 2024

Adding a JAK inhibitor to checkpoint immunotherapy in blood cancer patients may counter the negative effects of prolonged inflammation on tumour responses and improve outcomes, a US study suggests.

Published in Science (link here) a phase 1/2 trial in patients with relapsed/refractory Hodgkin’s lymphoma (r/r HL) showed that a combination of ruxolitinib with the anti–PD-1 antibody nivolumab resulted in improved clinical efficacy in patients who had previously failed checkpoint blockade immunotherapy

The findings support the concept that persistent inflammation driven by cytokines from immunotherapy may lead to  immunosuppression and disease relapse, said the research team from The Scripps Research Institute, California.

Since T cell exhaustion limits current responses to immunotherapy, the team showed in preclinical work that a small molecule JAK inhibitor could enhance antitumour T cell responses and improve the efficacy of immune checkpoint inhibitor (ICI) immunotherapy in animal models of cancer.

They followed this with a phase I clinical trial, in which 19 patients with r/r HL after prior checkpoint inhibitor immunotherapy were given ruxolitinib in combination with nivolumab.

The combination yielded a best overall response rate of 53%, with six of the 19 patients achieving a complete metabolic response to therapy.

Clinical response correlated with reductions in neutrophil-to-lymphocyte ratios (NLRs), percentages of suppressive myeloid cells, and increases in the numbers of cytokine-producing T cells after ruxolitinib treatment.

The study investigators noted that in both preclinical models and patient samples, the transcriptomic signature of  JAK-dependent cytokine G-CSF signalling was significantly down-regulated by ruxolitinib.

This suggested that “ruxolitinib may prevent suppressive programming of myeloid cells owing to excessive JAK–signal transducer and activator of transcription (STAT) signaling by cytokines such as G-CSF,” they wrote.

The authors said ruxolitinib rescued the function of exhausted T cells and enhanced the efficacy of immune checkpoint blockade in preclinical solid tumour and lymphoma models.

“This synergy was characterised by a switch from suppressive to immunostimulatory myeloid cells, which enhanced T cell division,” they commented.

“A lot of this started about 11 years ago, when we originally found that blocking a cytokine that signals through the JAK/STAT pathway, type 1 interferon, can promote immune responses and hasten virus clearance,” said co-senior author Professor John Teijaro, of the Department of Immunology and Microbiology at Scripps Research.

He said  high numbers of myeloid suppressor cells cause weak responses to immune checkpoint inhibitors, and  – along with a high ratio of neutrophil-to-lymphocyte cells – were associated with poor prognosis of several cancers, including Hodgkin lymphoma. But using the ruxolitinib combination therapy resulted in a reduction of both indicators, while also promoting functional T cells.

“We’re now enlisting myeloid cells as helpers for immunotherapy, as it seems that in order for T cells to increase in number and functionality, ruxolitinib needs to modulate the myeloid cells,” said Dr Teijaro.

First author Dr Jaroslav Zak, a postdoctoral fellow at Scripps Research said the new line of investigation may offer treatment possibilities for the 10% to 20% of patients with HL who don’t respond to checkpoint inhibitors.

He said it was promising that 87% of patients in the trial were still alive, and 46% stopped exhibiting signs of cancer progression altogether.

“Anecdotally, we know for sure that at least one patient had a very good response that lasted beyond the two years of the clinical trial,” says Zak. “Unlike chemotherapy, this treatment didn’t just slow down the disease but actually reversed it.”

“Ruxolitinib is actually an immunosuppressive drug that’s clinically approved for chronic graft-versus-host disease, so the fact that we saw immune-enhancing effects in patients treated with this drug using combination therapy was definitely surprising,” said Dr Zak. “This suggests that some drugs can actually have immune-enhancing effects, even if their primary indication is to relieve inflammatory disease pathology.”

A second study published in the same journal showed a similar effect of adding the JAK inhibitor itacitinib in enhancing the effect of  anti–PD-1 pembrolizumab in patients metastatic non–small cell lung cancer (NSCLC).

Patients showed an overall response rate of 67% and median progression-free survival of 23.8 months.  These outcomes were favourable compared to usual 45% response rates seen in this patient group, the study investigators said.

The best responders were those who had either low baseline inflammation or high baseline inflammation that responded to the JAK1 inhibitor treatment, they noted.

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