Checkpoint inhibitor therapies can be thought of as the molecular “brake release” for the immune system. These drugs eliminate the protein barriers that block the immune system from recognizing and targeting cancer cells in the body. While there are multiple checkpoint inhibitors approved to treat different types of cancer, many patients don’t respond, or they develop resistance to available treatment options.
A Scripps Research team has now found that the Janus kinase (JAK) inhibitor ruxolitinib, an approved immunosuppressive drug, supercharged T-cell responses when used alongside immune checkpoint inhibitors, boosting their effectiveness in fighting cancer. The researchers reported on studies in multiple preclinical infection and cancer models, and on findings from a Phase I clinical trial evaluating ruxolitinib with the anti–PD-1 immunotherapy nivolumab in Hodgkin lymphoma patients who relapsed or were refractory following checkpoint inhibitor immunotherapy.
“There’s a lot of activity in developing the next generation of immunotherapies, and we’re looking beyond therapeutics that target T cells directly,” said co-senior author John Teijaro, PhD, a professor in the Department of Immunology and Microbiology at Scripps Research. “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. 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.”
Teijaro is co-senior author of the team’s published paper in Science, in which they report on their preclinical studies and Phase I clinical trial, in a report titled, “JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma.” In their report and research article summary, the team stated, “Ruxolitinib rescued the function of exhausted T cells and enhanced the efficacy of immune checkpoint blockade in preclinical solid tumor and lymphoma models … Our results support the therapeutic potential of small-molecule JAK inhibition in combination with checkpoint inhibitors in cancer.”
T cells are produced by the immune system to fight off infections, as well as cancer. While “unleashing antitumor T cell activity by checkpoint inhibitor immunotherapy is effective in cancer patients,” the authors wrote, “clinical responses are limited.” Patients often stop responding to checkpoint immunotherapy when their T cells begin to wane. This phenomenon, called T-cell exhaustion, happens as T cells become chronically exposed to cancer cells. But based on the results of previous work, Teijaro and his research team wondered whether a JAK inhibitor such as ruxolitinib could increase T-cell production, while also improving checkpoint inhibitors and their brake release effects.
JAK enzymes are important parts of the JAK/signal transducer and activator of the transcription (STAT) pathway—a chain of interactions between cells and proteins that are essential for immune cell development. Dysregulation of the pathway is associated with both inflammation and cancer. JAK inhibitors (JAKis) restrict signals believed to cause inflammation, resulting in the immune system “calming down.” Moreover, the authors wrote, “Cytokine signaling through the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway correlates with checkpoint immunotherapy resistance.”
“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 Teijaro. Although JAK inhibitors are typically used to treat inflammatory diseases, there’s a known genetic link between JAK mutations and cancer, he added. However, the authors stated, “Despite known genetic links between JAK mutations and cancer, mainstream use of JAKis for cancer treatment has been impeded by JAKis’ immune-suppressive properties.”
Teijaro and colleagues established a screening strategy to discover small molecules that might rescue T-cell exhaustion. They turned to ReFRAME, a drug repurposing library built by Calibr-Skaggs, the drug discovery and development arm of Scripps Research. ReFRAME permits researchers to rapidly sort through thousands of existing FDA-approved drugs and determine if they could treat any other major illnesses. Using ReFRAME, the researchers identified the JAK inhibitor ruxolitinib as a contender.
Through a range of preclinical studies in mouse models of various forms of cancer and persistent viral infections, the researchers found that compared with immune checkpoint inhibitor (ICI) therapy alone, combining immunotherapy with ruxolitinib increased both the number of T cells and natural killer (NK) cells—another type of immune cell that limits the spread of cancer. “Notably, this combination was effective in multiple solid tumor and lymphoma models, including those without prior ICI resistance and those in which ruxolitinib monotherapy had no effect on tumor growth,” the team reported.
With this preclinical data in hand, the team partnered with Veronika Bachanova, MD, PhD, at the University of Minnesota, who had initiated a Phase I clinical trial of 19 patients with Hodgkin lymphoma who failed to respond to checkpoint inhibitors or relapsed following an initial 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,” explained first author Jaroslav Zak, PhD, a postdoctoral fellow at Scripps Research. “It’s very difficult to treat these patients.”
The Phase I study results showed that two years after starting a treatment regimen that combined ruxolitinib with the checkpoint inhibitor nivolumab—a current standard of care—87% of patients were still alive, and 46% stopped exhibiting signs of cancer progression altogether. “The combination yielded a best overall response rate of 53% with 6/19 patients achieving a complete metabolic response to therapy,” the investigators reported.
“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,” said Zak. “Unlike chemotherapy, this treatment didn’t just slow down the disease but actually reversed it.”
Myeloid cells, a type of immune cell from the bone marrow, are among the body’s most important lines of defense against infection. But cancer cells often hijack myeloid cells, which leads to tumor growth and metastasis. A high number of myeloid suppressor cells—which are found in many types of tumors and cause weak responses to immune checkpoint inhibitors—as well as a high ratio of neutrophil-to-lymphocyte cells are tied to 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.
“Ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and percentages of myeloid suppressor cells but increased numbers of cytokine-producing T cells,” the authors stated. “Given the occurrence of suppressive myeloid cells in various tumor types and adverse interference with immunotherapy, it is possible that JAK inhibition could improve checkpoint responses in other malignancies.” Teijaro added, “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.”
The overall findings were unexpected. Past research showed that ruxolitinib didn’t work on its own to treat cancer. “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,” continued Zak. “This suggests that some drugs can actually have immune-enhancing effects, even if their primary indication is to relieve inflammatory disease pathology.” As the authors also noted, “We demonstrate that JAK inhibition is not immune suppressive but rather stimulatory, suggesting that the context of JAK inhibitor usage dictates the ultimate treatment outcome.”
Building on their success, the researchers plan to examine whether other JAK inhibitors are even more effective than ruxolitinib at treating cancer. They’re also designing clinical trials to test the efficacy of ruxolitinib combined with checkpoint inhibitors in other forms of cancer, including those with solid tumors. In their paper, the team stated, “… we demonstrate that rather than suppress essential antitumor immunity, small-molecule JAK inhibition synergizes with checkpoint blockade immunotherapy to reshape the myeloid cell compartment and enhance natural killer (NK) and T cell responses.” This therapeutic strategy, they suggested, “offers an avenue to explore in future clinical trials designed to overcome resistance to and/or enhance ICI therapy.”
