New research conducted at the University of Pittsburgh has provided an explanation for the resistance of metastatic uveal melanoma to traditional immunotherapies. Additionally, the study has shown that adoptive therapy, which entails the cultivation of a patient’s T cells ex vivo before reinfusing them, can effectively address this uncommon and aggressive form of cancer.In a recent article in Nature Communications, the researchers from the University of Pittsburgh also describe the development of a new clinical tool to predict which patients will benefit from adoptive therapy. This work, funded by UPMC Enterprises, aims to enhance personalized therapies and prevent ineffective treatments for metastatic uveal melanoma.
“The conventional belief was that uveal melanoma is a ‘cold’ cancer, meaning that T cells cannot enter these tumors,” explained senior author Dr. Udai Kammula, who is an associate professor of surgery at Pitt and the director of the Solid Tumor Cell Therapy Program at UPMC Hillman Cancer Center. “However, we demonstrate that T cells are indeed infiltrating metastases.”The immune cells in the tumor are being activated, but they are not able to function because something in the tumor is preventing them from doing so. Adoptive therapy helps to rescue these cells from the suppressive tumor environment and has been successful in treating some patients.
Uveal melanoma starts in the uveal tract of the eye but often spreads aggressively throughout the body, particularly to the liver. When metastasis occurs, it is extremely challenging to treat this cancer and the outlook for patients is usually very poor.
“Cutaneous melanoma, which affects the skin, is a prime example of the success of immunotherapy. It responds very well to this treatment.”Kammula stated, “Traditional immunotherapies like checkpoint inhibitor drugs have not been effective for uveal melanoma. The reasons for this were not clear until now.”
In a previous study published in Lancet Oncology, Kammula and his team performed adoptive therapy on 19 uveal melanoma patients. They surgically removed metastatic tumors and cultivated T cells from the tumors in the laboratory. When they reinfused these cells, 35% of the patients experienced either partial or complete regression of their cancer. This challenges the belief that cancer-fighting cells known as tumor-infiltrating lymphocytes (TILs) are not present in uveal melanoma. However, the reasons behind this phenomenon remained unknown.
Immune checkpoint inhibitors, which boost the activity of these T cells, are not effective in treating uveal melanoma.
Kammula discovered an opportunity to address this issue using a special resource that he and his team have been creating for the past ten years: the largest repository of uveal melanoma samples, corresponding tissues, and clinical information.
Upon analyzing 100 metastases from 84 patients, the researchers found that more than half of these tumors were packed with T cells. They then conducted single cell RNA sequencing to assess gene expression in nearly 100,000 cells from six m.Metastases. The researchers discovered that in some of these tumors, the tumor-infiltrating lymphocytes (TILs) were activated and able to attack tumor cells in a dish. However, they were not multiplying to high numbers within the tumor.
“We found that TILs from metastatic uveal melanoma can potentially attack the tumor, but something in the tumor microenvironment is inhibiting their activity, causing them to be in a dormant or quiescent state,” Kammula explained. “By removing these cells from the suppressive environment and growing them in the laboratory, we can restore their ability to fight the tumor when reintroduced into the patient.”
Despite this, TIL therapy does not work for everyone, as the research indicates.Researchers in their previous study found that predicting which patients will respond to treatment and which will not is crucial. Kammula and his co-author Shravan Leonard-Murali, M.D., created a clinical tool called Uveal Melanoma Immunogenic Score (UMIS) to address this issue. UMIS measures the tumor’s activity based on the expression of over 2,000 genes by tumor cells, immune cells, and other cells in the tumor microenvironment. UMIS values ranged from 0.114 to 0.347 among 100 metastases, with higher values indicating tumors with more potent TILs. In the earlier study, researchers also examined patients who received adoptive therapy.They discovered that patients with higher UMIS scores had better tumor regression, indicating that this biomarker might be able to predict which patients will respond. Additionally, they observed that patients with metastases scoring above 0.246 experienced significantly improved progression-free survival and overall survival compared to those with UMIS below this threshold. “If a patient’s UMIS level is below this cutoff, we believe that adoptive therapy is not suitable. Utilizing a biopsy to calculate a patient’s UMIS could help prevent useless therapies and unnecessary invasive procedures for patients,” Kammula stated. “However, the immune system is not static. UMIS provides insight into the tumor, which could help determine the best time for adoptive therapy treatment, similar to picking a fruit at its peak ripeness. Kammula is currently assessing the score in an ongoing TIL therapy clinical trial at Pitt for patients with metastatic uveal melanoma. Additionally, he and his team are using their findings from uveal melanoma to address challenging tumors like pancreatic cancer. They are also working on a pan-cancer version of UMIS to predict a patient’s likely response to adoptive therapy for any type of cancer.The study was conducted by a team from UPMC Hillman Cancer Center and University of Pittsburgh, including researchers Chetana Bhaskarla, Ghanshyam S. Yadav, Sudeep K. Maurya, Chenna R. Galivet, Joshua A. Tobin, Rachel J. Kann, Eishan Ashwat, Patrick S. Murphy, Anish B. Chakka, Vishal Soman, Paul G. Cantalupo, Xinming Zhuo, Gopi Vyas, Dara L. Kozak, Lindsey M. Kelly, Ed Smith, Uma R. Chandran, and Yen-Michael S. Hsu.
The study was supported by UPMC Enterprises, as well as other sources.The University of Pittsburgh’s Center for Research Computing, the National Institutes of Health (S10OD028483), the UPMC Hillman Cancer Center Immunologic Monitoring and Cellular Products Laboratory (CCSG P30 CA047904), and a National Cancer Institute training grant (T32CA113263) provided funding for this study.
Journal Reference:
- Shravan Leonard-Murali, Chetana Bhaskarla, Ghanshyam S. Yadav, Sudeep K. Maurya, Chenna R. Galiveti, Joshua A. Tobin, Rachel J. Kann, Eishan Ashwat, Patrick S. Murphy, Anish B. Chakka, Vishal Soman, Paul G. Cantalupo, Xinming Zhuo, Gopi Vyas, Dara L. Kozak, Lindsey M. Kelly, Ed Smith, Uma R. Chandran, Yen rnrnThe authors of a study published in Nature Communications, Michael S. Hsu and Udai S. Kammula, discuss the implications of uveal melanoma immunogenomics on the resistance and susceptibility to immunotherapy. The study was published in 2024 and can be found in volume 15, issue 1 of the journal. The DOI for the article is 10.1038/s41467-024-46906-4.