What do the eye and the liver have in common? They are seemingly dissimilar organs. The eye interfaces with the outside world, and its primary function is to transmit information to the brain. The liver, on the other hand, is internal, and plays a more active role. It filters and breaks down toxins, aids in digestion, regulates blood chemistry, and more. They both have critical biological functions, and they both maintain cautious, controlled immune environments to protect those functions.
The immune system exists to protect us, but excessive immune activation and inflammation can be damaging. Too much swelling or cell death in an organ can end up impairing its function. The immune system has safeguards in place – regulatory cells and immunosuppressive molecules – that keep active immune cells in check by putting them to sleep when they’re not needed. These safeguards are especially strong in the eye and the liver, for good reason. They prevent swelling and other tissue changes to preserve vision in the eye, and they ensure the liver doesn’t overreact to the myriad potentially inflammatory products it encounters in its normal function. Keeping immune cells at bay, however, is not so helpful when malignancies arise.
Uveal melanoma is a rare cancer that occurs in the eye. The cancer metastasizes in approximately half of cases, and when it spreads, it almost always spreads to the liver. The cautious, controlled immune system in the liver allows cancer growth to proceed undetected and unchallenged, sometimes for decades after the initial diagnosis. Metastatic uveal melanoma is hard to treat, and prognosis is poor, with an average survival time of only 10 months. While immunotherapies, which bolster the body’s own immune system to kill cancerous cells, have improved treatment options for many cancers including melanoma that arises from the skin, they are not effective in treating uveal melanoma because the immune cells near the cancer, in the eye and liver, appear even more difficult to reactivate.
Dr. Shailender Bhatia, Dr. Natalie Miller, and colleagues in the Clinical Research Division at Fred Hutch are investigating new treatment strategies to improve outcomes for uveal melanoma patients. One strategy that has shown some success is hepatic transarterial immunoembolization (TAIE). In short, this involves administering immune activating molecules directly to the liver to wake up the immune cells there so they can recognize and attack cancerous cells. The directed approach prevents overwhelming immune activation, and potential damage, elsewhere in the body. Dr. Bhatia and his team, working closely with Dr. Wayne Monsky in Interventional Radiology, hypothesized that combining TAIE with a systemic immune checkpoint inhibitor immunotherapy, which enhances immune cells’ ability to detect and kill cancer cells throughout the body, may lead to improved cancer control beyond what either therapy affords on its own.
In a recently published study in Cancer Immunology, Immunotherapy, the team evaluated the efficacy and safety of the combined TAIE and systemic immunotherapy approach. They retrospectively analyzed the outcomes of 18 patients with metastatic uveal melanoma who received TAIE with or without immune checkpoint inhibitors at Fred Hutch Cancer Center and the University of Washington from 2016 to 2023. The results were promising: 10 out of the 18 patients responded to the treatment, with disease either improving (tumors shrinking) or remaining stable for some time. Interestingly, all patients that saw disease improvement received the combination therapy of TAIE with systemic immune checkpoint inhibitors. Dr. Bhatia commented, “The average survival in our study was 35 months, which compares favorably to the reported survival rates in most modern trials in this disease. Encouragingly, some patients have derived sustained long-term benefit even after discontinuation of therapy, which is seldom seen with conventional therapy approaches used in this disease.”
These results “suggest possible synergy of a liver-directed immunotherapy with systemic immune checkpoint inhibitors in overcoming immune evasion in a cancer type with a unique propensity to metastasize to the liver.” Liver-directed, combination immunotherapies may well be the future of metastatic uveal melanoma treatment. Dr. Bhatia and his team are excited about the numerous upcoming clinical trials investigating the direct delivery of promising immunotherapy drugs to liver tumors. By testing various strategies, there’s hope of finding a combination of therapies that very effectively treats this disease.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Natalie Miller, Joshua Veatch, Evan Hall, and Shailender Bhatia contributed to this research.
The spotlighted research was funded by the Jacob Greene Foundation and the National Cancer Institute.
Miller NJ, Kwan SW, Leary JB, Hippe DS, McCamy W, Veatch JR, Hall ET, Monsky WL, Bhatia S. 2025. Concurrent treatment with transarterial immunoembolization of hepatic metastases and systemic immune checkpoint inhibitors to overcome immune evasion in patients with metastatic uveal melanoma. Cancer Immunology, Immunotherapy. doi: 10.1007/s00262-025-04124-x
Science Spotlight writer Ashley Person is a PhD candidate in the Cohn lab in the Vaccine and Infectious Disease Division at Fred Hutch. She studies how HIV-infected cells persist over time in people living with HIV on long term treatment.