Distinct immune “signatures” found in patients who experience negative reactions while undergoing cancer immunotherapy may aid doctors in identifying those at risk, enabling earlier intervention to prevent severe side effects, according to a recent study conducted by researchers from the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.
Distinct immune “signatures” found in patients who experience negative reactions while undergoing cancer immunotherapy may aid doctors in identifying those at risk, enabling earlier intervention to prevent severe side effects, according to a recent study conducted by researchers from the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.
The research, which was published on October 15 in the Journal of Clinical Investigation, is the most extensive study to date examining immune signatures across various cancers. It involved a diverse group of 111 patients treated with immune checkpoint inhibitors—substances that help to activate the body’s natural defenses against cancer. Approximately 40% of these patients developed immune-related side effects, a finding that was anticipated. However, those experiencing these effects were more inclined to have a history of autoimmune diseases and were treated with a combination of immune checkpoint inhibitors. The researchers also identified a unique immune “signature” in patients who later exhibited adverse events.
“Increased levels of white blood cells referred to as T-helper 2 (Th2) and T-helper 17 (Th17), along with their related cytokines, were observed before the onset of immune-related side effects, highlighting them as potential targets for treatment,” explains Mark Yarchoan, M.D., the principal author of the study and an associate professor of oncology at the Johns Hopkins Kimmel Cancer Center. Won Jin Ho, M.D., also played a vital role as the co-senior author and is the director of the Mass Cytometry Facility and the associate director of the Convergence Institute at the same center.
Immunotherapy has significantly improved outcomes for numerous cancer patients. Yet, some individuals treated with immune checkpoint inhibitors face serious negative effects that can lead to long-lasting disabilities or may even be fatal. According to Yarchoan, for patients with advanced stages of cancer who have tried all other options, the benefits of immunotherapy often outweigh the risks.
“The decision becomes increasingly complex when these drugs are administered to patients with potentially curable cancers during earlier stages of disease,” he states. “We often find cases where patients are cured of cancer but suffer long-term debilitating effects from the therapy.”
To manage these side effects, oncologists typically use medications designed for treating arthritis or other autoimmune issues. However, the precise mechanisms that cause these adverse effects are still not fully understood, nor is there a clear treatment protocol, Yarchoan mentions. Previous research has looked into these adverse effects predominantly in skin cancer patients, failing to include many Black patients, who have a lower incidence of skin cancer. Yarchoan and colleagues aimed to deepen their understanding by studying a more representative patient sample from the Johns Hopkins Kimmel Cancer Center.
They found that increases in Th2 and Th17 levels served as an early warning for imminent adverse effects. Additionally, elevated levels of the cytokine interleukin 6 (IL-6), an anti-inflammatory protein produced by immune cells, emerged as the strongest predictor for which patients were likely to experience immune-related adverse events. Higher IL-6 levels also correlated with poorer outcomes from cancer therapy.
“IL-6 seems to serve a dual purpose,” notes Ho. “It may contribute to both cancer progression and the promotion of immune adverse events. Our findings strongly advocate for the application of IL-6 inhibitors in the treatment and prevention of these adverse effects.”
Aliyah Pabani, M.D., M.P.H., an assistant professor of oncology and co-director of the Immune-Related Toxicity Team at the Johns Hopkins Kimmel Cancer Center, has initiated a clinical trial to evaluate whether patients who previously had to stop using immune checkpoint inhibitors due to immune-related side effects can safely resume them if they also take IL-6 inhibitors to help avoid those events.
“This is an excellent example of the Kimmel Cancer Center team’s approach from laboratory research to patient care,” Pabani remarks. “We are making swift advancements to translate our discoveries into enhanced therapies for our patients.”
Yarchoan, Ho, and their team plan to expand their research by enrolling 500 additional patients to confirm their findings and gather more specific information about the immune signatures tied to individual types of immune-related adverse events. For instance, they want to explore whether the cytokines that provoke arthritis are the same as those responsible for liver inflammation.
The study included contributions from co-authors Chester Kao, Soren Charmsaz, Stephanie Alden, Madelena Brancati, Howard Li, Aanika Balaji, Kabeer Munjal, Kathryn Howe, Sarah Mitchell, James Leatherman, Ervin Griffin, Mari Nakazawa, Hua-Ling Tsai, Ludmila Danilova, Chris Thoburn, Jennifer Gizzi, Nicole Gross, Alexei Hernandez, Erin Coyne, Sarah Shin, Jayalaxmi Suresh Babu, George Apostol, Jennifer Durham, Brian Christmas, Maximilian Konig, Evan Lipson, Jarushka Naidoo, Laura Cappelli, Aliyah Pabani, Yasser Ged, Marina Baretti, Julie Brahmer, Jean Hoffman-Censits, Tanguy Seiwert, Elizabeth Jaffee, and Won Jin Ho from Johns Hopkins. Researchers from Beaumont Hospital and RCSI University Health Sciences in Dublin, Ireland, as well as representatives from F. Hoffman-La Roche Ltd. and Genentech Inc., also lent their expertise.
The research received financial support from the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, the National Cancer Institute, the National Institutes of Health, Swim Across America, the National Institute of Arthritis and Musculoskeletal Diseases, and the immunotherapy Centers of Research Excellence (imCORE) Network-Genentech.
Yarchoan has received grant and research support for Johns Hopkins from companies including Bristol-Myers Squibb, Exelixis, Incyte, and Genentech. He also receives honoraria from Exelixis, AstraZeneca, Replimune, Hepion Pharmaceuticals, Lantheus, Genentech, and Incyte. He has co-invented patents related to therapeutic cancer vaccines and is a co-founder with equity in Adventris Pharmaceuticals, outside of the work described here. All relationships are managed according to The Johns Hopkins University’s conflict-of-interest policies.
