Researchers may have uncovered the mechanisms behind conventional immunotherapy resistance as well as the efficacy of adoptive therapy in metastatic uveal melanoma, according to a recent study published by Leonard-Murali et al in Nature Communications. The findings demonstrated the potential to improve personalized therapies and avoid unnecessary treatments in metastatic uveal melanoma.
Background
Uveal melanoma is a rare and aggressive type of cancer that originates in the uveal tract of the eye but tends to metastasize throughout the body, often to the liver. When metastasis occurs, the disease may become challenging to treat and the prognosis for patients is almost always poor.
“Cutaneous melanoma, which affects the skin, is the poster child of immunotherapy. It responds incredibly well to immune checkpoint inhibitor drugs,” explained senior study author Udai Kammula, MD, FACS, Associate Professor of Surgery at the University of Pittsburgh and Director of the Solid Tumor Cell Therapy Program at the UPMC Hillman Cancer Center. “None of these conventional immunotherapies work for uveal melanoma, but we hadn’t known why until now,” he added.
“The dogma was that uveal melanoma is a ‘cold’ cancer, meaning that T cells can’t get into these tumors,” noted Dr. Kammula. “We show that T cells are in fact infiltrating metastases and they’re getting activated, but they’re just sitting there in a dormant state because something in the tumor is suppressing them. Adoptive therapy allows us to rescue these cells from the suppressive tumor microenvironment and successfully treat some patients,” he said. Adoptive therapy requires growing a patient’s T cells outside the body prior to reinfusing them.
Previous research published by Chandran et al in The Lancet Oncology involved the use of adoptive therapy to surgically extract tumors from 19 patients with metastatic uveal melanoma and grow T cells from the tumors in a laboratory. After reinfusing the cells, 35% of the patients achieved either a partial or complete regression of their cancer—evidence against the assumption that tumor-infiltrating lymphocytes aren’t found in uveal melanoma. However, the researchers were still uncertain of why immune checkpoint inhibitors were ineffective in these patients.
Study Methods and Results
In the recent study, the researchers used one of the largest repositories of uveal melanoma samples, corresponding tissues, and clinical information to analyze 100 metastases from 84 patients. They discovered that there were T cells present in over 50% of the tumors. The researchers then performed single-cell RNA sequencing to measure gene expression in nearly 100,000 cells from six metastases. They found that the tumor-infiltrating lymphocytes in some of these tumors were activated and capable of attacking tumor cells in a dish, but they weren’t proliferating to high numbers within the tumors.
“We found that [tumor-infiltrating lymphocytes] from metastatic uveal melanoma have the potential to attack the tumor, but something in the tumor microenvironment is shutting them down, so they’re in a dormant or quiescent state. By liberating these cells from the suppressive environment and growing them in the lab, we can rescue their tumor-fighting capacity when infused back into the patient,” explained Dr. Kammula.
Because tumor-infiltrating lymphocyte therapy is known to be ineffective in some patients, the researchers developed a novel clinical tool called the Uveal Melanoma Immunogenic Score—a holistic measure of the tumor that designed to reflect the activity of over 2,000 genes expressed by the tumor cells, immune cells, and other cells in the tumor microenvironment—in order to predict which patients were most likely to respond to therapy. The scores ranged from 0.114 to 0.347 across 100 metastases, with higher values indicating tumors with more potent tumor-infiltrating lymphocytes.
After examining the patients who received adoptive therapy in the previous study, the researchers revealed that those with higher measures of tumor-infiltrating lymphocytes on the Uveal Melanoma Immunogenic Score experienced better tumor regression, suggesting that the new biomarker may be capable of predicting response to therapy. They also found that the patients with metastases scoring above 0.246 had significantly improved progression-free survival and overall survival compared with those who scored below the cutoff.
Conclusions
“If a patient’s [Uveal Melanoma Immunogenic Score] level is below this threshold, we think that adoptive therapy is not appropriate. Using a biopsy to calculate a patient’s [score] could help avoid futile therapies and unnecessarily subjecting patients to invasive operations, [b]ut the immune system is not static. [The Uveal Melanoma Immunogenic Score] offers a window into the tumor that could also help us find the optimal time to treat a patient with adoptive therapy,” underscored Dr. Kammula.
The researchers are currently evaluating the Uveal Melanoma Immunogenic Score prospectively in an ongoing tumor-infiltrating lymphocyte therapy clinical trial involving patients with metastatic uveal melanoma. They also plan to apply their findings to other cancer types such as pancreatic cancer and are developing a pan-cancer version of the Uveal Melanoma Immunogenic Score to predict response to adoptive therapy in patients with any type of cancer.
Disclosure: The research in this study was supported by UPMC Enterprises and in part by the Pitt Center for Research Computing, the National Institutes of Health, the UPMC Hillman Cancer Center Immunologic Monitoring and Cellular Products Laboratory, and a National Cancer Institute training grant. For full disclosures of the study authors, visit nature.com.
