New research from the University of Pittsburgh reveals why metastatic uveal melanoma is resistant to traditional immunotherapies and how adoptive therapy, involving growing a patient’s T cells outside the body before reinfusing them, can effectively treat this aggressive cancer. The study, published in Nature Communications, also introduces a new clinical tool that predicts which patients will respond to adoptive therapy, enhancing personalized treatments and avoiding futile interventions for metastatic uveal melanoma. This research, supported by UPMC Enterprises, sheds light on the mechanisms behind the disease and offers promising treatment options.
Uveal melanoma, which originates in the eye’s uveal tract, has a tendency to spread rapidly throughout the body, especially to the liver, making it challenging to treat and often resulting in poor patient outcomes. Unlike cutaneous melanoma, which responds well to immune checkpoint inhibitor drugs, uveal melanoma has been resistant to conventional immunotherapies. However, a recent Lancet Oncology study showed that adoptive therapy was successful in treating some uveal melanoma patients, highlighting the presence of tumor-infiltrating lymphocytes (TILs) in these tumors. But the reasons behind the ineffectiveness of immune checkpoint inhibitors in treating this cancer remained unclear until now.
By analyzing a repository of uveal melanoma samples and corresponding clinical data, researchers found that T cells are present in metastatic tumors, but they are suppressed within the tumor microenvironment, preventing their effective function. Utilizing single-cell RNA sequencing, the team identified that TILs in these metastatic tumors were capable of attacking tumor cells but were in a dormant state due to the suppressive environment. Adoptive therapy offers a way to rescue these cells, grow them outside the body, and reintroduce them into the patient, enabling them to effectively fight the cancer.
To determine which patients are likely to respond to adoptive therapy, the researchers developed a clinical tool called Uveal Melanoma Immunogenic Score (UMIS), which assesses tumor activity based on the expression of over 2,000 genes. Patients with higher UMIS scores had better outcomes, including improved regression rates, progression-free survival, and overall survival. This biomarker could help identify patients who are suitable candidates for adoptive therapy, potentially avoiding ineffective treatments and unnecessary procedures. UMIS also provides insights into the optimal timing for treatment, ensuring the most beneficial outcomes for patients.
The researchers are currently evaluating UMIS in a clinical trial for patients with metastatic uveal melanoma, aiming to validate its predictive value in real-time treatment settings. They are also applying their findings from uveal melanoma to other challenging tumors like pancreatic cancer, developing a pan-cancer version of UMIS to assess responses to adoptive therapy in various cancer types. With support from UPMC Enterprises and other funding sources, this research contributes to advancing personalized treatment strategies and improving outcomes for patients with aggressive cancers. Through innovative approaches like adoptive therapy and predictive biomarkers, researchers are paving the way for more effective and targeted cancer treatments.
