Checkpoint inhibitor therapies can be likened to releasing the molecular “brake” on the immune system. These drugs eliminate protein barriers that typically hinder the immune system from identifying and attacking cancer cells in the body. Despite several approved checkpoint inhibitors for various cancers, many patients do not respond well or develop resistance to existing treatments.
A team from Scripps Research has discovered that ruxolitinib, an approved immunosuppressive drug, enhances T-cell responses when used alongside checkpoint inhibitors, significantly boosting their efficacy against cancer. Published in Science, these findings are reinforced by a Phase I clinical trial involving Hodgkin lymphoma patients and preclinical models, titled “JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma.”
“We are actively advancing the development of next-generation immunotherapies that extend beyond direct T-cell targeting,” said co-senior author John Teijaro, Ph.D., a professor at Scripps Research’s Department of Immunology and Microbiology.
T cells, crucial for combating infections and cancer, often become ineffective in responding to checkpoint immunotherapy due to a condition known as T-cell exhaustion, where prolonged exposure to cancer cells hampers their function. Building on previous findings, Teijaro and his team explored whether a JAK inhibitor like ruxolitinib could not only enhance T-cell production but also improve the effects of checkpoint inhibitors and their immune-boosting capabilities.
JAK enzymes are integral to the JAK/signal transducer and activator of transcription (STAT) pathway, essential for immune cell development. Dysregulation of this pathway is associated with inflammation and cancer. JAK inhibitors mitigate signals that trigger inflammation, thereby calming the immune response.
The researchers leveraged ReFRAME, a drug repurposing library by Calibr-Skaggs at Scripps Research, to identify ruxolitinib among existing FDA-approved drugs capable of restoring exhausted T-cell function. In various preclinical models involving mice with different cancers and persistent viral infections, combining ruxolitinib with checkpoint therapy increased the numbers of T cells and natural killer (NK) cells, which combat cancer spread.
Partnering with Dr. Veronika Bachanova at the University of Minnesota, the team conducted a Phase I clinical trial involving 19 Hodgkin lymphoma patients who had not responded to or relapsed after initial checkpoint inhibitor treatments.
“Less than 20% of cancer patients respond to checkpoint inhibitors, including 10% to 20% of Hodgkin lymphoma patients. These individuals often resort to non-curative chemotherapy,” explained lead author Jaroslav Zak, a postdoctoral fellow at Scripps Research.
After two years of combining ruxolitinib with nivolumab, a standard checkpoint inhibitor, 87% of patients were still alive, and 46% showed no signs of cancer progression. Zak highlighted a patient who exhibited a durable response beyond the trial period, unlike chemotherapy, which merely slows disease progression.
Myeloid cells, vital in immune defense, are often hijacked by cancer cells to promote tumor growth. Ruxolitinib combination therapy reduced myeloid suppressor cells and improved the ratio of neutrophil-to-lymphocyte cells, which are indicative of cancer prognosis in Hodgkin lymphoma.
“Modulating myeloid cells with ruxolitinib appears crucial for increasing T-cell numbers and functionality,” Teijaro noted, underscoring unexpected immune-enhancing effects of ruxolitinib, originally an immunosuppressive drug approved for chronic graft-versus-host disease.
Encouraged by their findings, the team plans to explore more potent JAK inhibitors than ruxolitinib and design clinical trials to assess the combination’s efficacy in other cancers resistant to immunotherapy.
“It’s uncommon to combine preclinical data with clinical trial results in a single paper,” Teijaro remarked. “Our findings are particularly promising as patients are already benefiting from this combination, suggesting broad applicability to resistant cancers.”
