Research scientists have discovered that combining the immunosuppressive drug ruxolitinib with existing checkpoint inhibitor therapies can boost the effectiveness of cancer treatment, especially for Hodgkin lymphoma. Checkpoint inhibitors work by removing the barriers that prevent the immune system from identifying and attacking cancer cells in the body.
Checkpoint inhibitors serve as a molecular “brake release” for the immune system, eliminating protein obstacles that hinder the recognition and targeting of cancer cells. Despite several approved checkpoint inhibitors for various cancers, many patients do not respond well or develop resistance to the available treatments.
A team of researchers from Scripps Research has found that ruxolitinib, an approved immunosuppressive drug, enhances T-cell responses when combined with checkpoint inhibitors, thereby improving their effectiveness against cancer. These findings, published in Science on June 21, were supported by a phase I clinical trial involving Hodgkin lymphoma patients and preclinical studies.
“There is a growing interest in developing advanced immunotherapies beyond direct T-cell targeting therapeutics,” says co-senior author John Teijaro, PhD, a professor in the Department of Immunology and Microbiology at Scripps Research.
T cells play a crucial role in combating infections and cancer. Patients often become unresponsive to checkpoint immunotherapy when their T cell levels decline, a condition known as T-cell exhaustion. This occurs when T cells are continuously exposed to cancer cells. Based on previous research, Teijaro and his team explored whether a JAK inhibitor like ruxolitinib could enhance T-cell production and improve checkpoint inhibitor effects.
JAK enzymes are key components of the JAK/signal transducer and activator of transcription (STAT) pathway, which is vital for immune cell development. Dysregulation of this pathway is linked to inflammation and cancer. JAK inhibitors block signals that trigger inflammation, leading to immune system regulation.
“Our research began about 11 years ago when we discovered that blocking a cytokine signaling through the JAK/STAT pathway could boost immune responses and expedite virus clearance,” Teijaro explains. Although JAK inhibitors are mainly used for inflammatory conditions, there is a known genetic association between JAK mutations and cancer.
To identify existing JAK inhibitors that could restore exhausted T cell function, the researchers utilized the drug repurposing library ReFRAME developed by Calibr-Skaggs, the drug discovery division of Scripps Research. ReFRAME allows researchers to quickly screen thousands of FDA-approved drugs to identify potential treatments for various diseases. Through this platform, ruxolitinib emerged as a promising candidate.
Through various preclinical models involving mice with different cancer types and chronic viral infections, the researchers demonstrated that combining ruxolitinib with checkpoint therapy increased the number of T cells and natural killer (NK) cells, which also play a role in limiting cancer spread.
Benefiting from the preclinical data, the team collaborated with Dr. Veronika Bachanova at the University of Minnesota, who conducted a phase I clinical trial with 19 Hodgkin lymphoma patients who did not respond to or relapsed after initial checkpoint inhibitor treatment.
“Less than 20% of cancer patients respond to checkpoint inhibitors, underscoring the challenges in treatment. Even in cancers like Hodgkin lymphoma, where checkpoint inhibitors are typically effective, about 10% to 20% of patients do not respond and require nonspecific chemotherapy,” says first author Jaroslav Zak, a postdoctoral researcher at Scripps Research. “Treating these patients is particularly challenging.”
After commencing a treatment regimen combining ruxolitinib with the checkpoint inhibitor nivolumab, a standard therapy, 87% of patients were still alive after two years, with 46% showing no signs of cancer progression.
One patient, in particular, exhibited a remarkable response that persisted beyond the trial period. Unlike chemotherapy, this treatment not only slowed down the disease but also reversed it.
Myeloid cells, originating from the bone marrow, play a crucial role in immune defense against infections. Cancer cells often manipulate myeloid cells, leading to tumor growth and spreading. Elevated levels of myeloid suppressor cells and a high ratio of neutrophil-to-lymphocyte cells are linked to poor outcomes in several types of cancer, including Hodgkin lymphoma. However, combining ruxolitinib therapy reduced these indicators while enhancing functional T cells.
“We are now enlisting myeloid cells to support immunotherapy, as it appears that modulating myeloid cells is crucial for increasing the number and functionality of T cells,” Teijaro explains.
These unexpected findings challenge previous research that suggested ruxolitinib alone was ineffective in treating cancer.
“Ruxolitinib is an immunosuppressive drug approved for chronic graft-versus-host disease. It was surprising to observe immune-boosting effects in patients receiving this drug in combination therapy,” Zak notes. “This indicates that certain drugs may have immune-enhancing properties even when primarily prescribed to alleviate inflammation.”
Building on this success, the researchers intend to investigate if other JAK inhibitors are more potent than ruxolitinib in cancer therapy. They are also planning clinical trials to assess the efficacy of combining ruxolitinib with checkpoint inhibitors in different cancer types, including solid tumors.
“Having both preclinical data and a clinical trial supporting evidence in one study is quite rare,” Teijaro remarks. “In my decades-long career, I have never encountered such a comprehensive validation of our findings. These results are particularly encouraging as we are already witnessing patient benefits from this combination therapy, which we believe can be applied to many resistant cancers.”
This study and the researchers involved received support from funding provided by Bristol-Myers Squibb (grant CA209-9EF), the Cancer Research Institute/Irvington Postdoctoral Fellowship, Incyte Corporation (grant IST-USA-000382), and the National Institutes of Health (grants R01AI123210, R01AI164744, R21AI141842, and UL1TR002550 Pilot Award).
