Treatments using checkpoint inhibitors can be compared to the immune system’s molecular “brake release.” These medications remove the protein barriers that prevent the body’s immune system from identifying and attacking cancer cells. Even though several checkpoint inhibitors have been licenced to treat various cancer types, many patients either don’t react to the existing regimens or develop resistance to them.
Researchers at Scripps Research have recently discovered that when taken with checkpoint inhibitors, the immunosuppressive medication ruxolitinib, which is licenced, enhanced T-cell responses and increased the drugs’ ability to fight cancer. Preclinical models and a phase I clinical study including patients with Hodgkin lymphoma corroborate these findings, which were published in Science.
There’s a lot of activity in developing the next generation of immunotherapies, and we’re looking beyond therapeutics that target T cells directly.
John Teijaro, PhD
The immune system produces T cells to combat both cancer and infections. When a patient’s T cells start to decline, checkpoint immunotherapy typically stops working for them. T cells experience a condition known as T-cell fatigue when they are repeatedly exposed to cancer cells. Teijaro and his colleagues, however, were curious as to whether a JAK inhibitor, such as ruxolitinib, might boost T-cell production in addition to enhancing checkpoint inhibitors and their “brake release” effects. This was based on the findings of earlier research.
Important components of the JAK/STAT pathway, which is a series of interactions between cells and proteins necessary for the formation of immune cells, include JAK enzymes. Inflammation and cancer are linked to the pathway’s dysregulation. JAK inhibitors block signals thought to be inflammatory, which causes the immune system to “calm down.”
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,
Although JAK inhibitors are typically used to treat inflammatory diseases, there’s a known genetic link between JAK mutations and cancer.
John Teijaro
Teijaro and his colleagues used ReFRAME, a drug repurposing library constructed by Calibr-Skaggs, the drug research and development division of Scripps Research, to ascertain whether already available JAK inhibitors may bring back the functionality of worn-out T cells. With ReFRAME, scientists can quickly sift through hundreds of FDA-approved medications now on the market to see whether they may be used to treat more serious disorders. The researchers determined that ruxolitinib was a potential candidate using ReFRAME.
In comparison to checkpoint therapy alone, the researchers found that combining the treatment with ruxolitinib increased the number of T cells and natural killer (NK) cells another type of immune cell that limits the spread of cancer through a variety of preclinical models in which mice had various forms of cancer and persistent viral infections.
Having obtained these preclinical results, the group collaborated with Veronika Bachanova, MD, PhD, of the University of Minnesota, who had started a phase I clinical trial involving 19 patients with Hodgkin lymphoma who either did not react to checkpoint inhibitors or had recurrence after the first response.
Among patients with all types of cancer, fewer than 20% respond to checkpoint inhibitors. Even in cancer types that typically respond well such as Hodgkin lymphoma, about 10% to 20% of patients don’t respond to checkpoint inhibitors, and they have to be treated with a chemotherapy that is fairly nonspecific and is not curative.
Jaroslav Zak
However, 87% of patients were still alive two years after beginning a therapy regimen that included the checkpoint inhibitor nivolumab together with ruxolitinib, which is currently the standard of care. Additionally, 46% of patients ceased displaying any symptoms of disease development.
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,
Unlike chemotherapy, this treatment didn’t just slow down the disease but actually reversed it.
Jaroslav Zak
One of the most crucial defence mechanisms the body has against infection is the myeloid cell, a kind of immune cell found in the bone marrow. However, myeloid cells are frequently taken over by cancer cells, which promotes the development and spread of tumours. A high ratio of neutrophils to lymphocytes and a large number of myeloid suppressor cells, which are present in many tumour types and result in weak responses to immune checkpoint inhibitors, are associated with poor prognoses for a variety of malignancies, including Hodgkin lymphoma. However, the ruxolitinib combination treatment reduced both markers and increased 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.
John Teijaro
However, these results were not predicted. First, prior studies have demonstrated that ruxolitinib was ineffective as a stand-alone cancer treatment.
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,
This suggests that some drugs can actually have immune-enhancing effects, even if their primary indication is to relieve inflammatory disease pathology.
Jaroslav Zak
Building on their achievements, the researchers want to find out if there are any further JAK inhibitors that can cure cancer even more successfully than ruxolitinib. Additionally, research trials are being designed to evaluate the effectiveness of ruxolitinib in conjunction with checkpoint inhibitors for cancers other than solid tumours.
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It’s very rare to have supporting evidence with preclinical data and a clinical trial in one paper,
I’ve been doing this for decades, and I’ve never had that happen in my career.” He continues, “our results are particularly exciting because we are already seeing patients benefit from the combination and we believe this could be applied to several immunotherapy resistant cancers.
John Teijaro
Source: Scripps Research News
Journal Reference: Zak, Jaroslav, et al. “JAK Inhibition Enhances Checkpoint Blockade Immunotherapy in Patients with Hodgkin Lymphoma.” Science, 2024, https://doi.org/10.1126/science.ade8520.
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