Background Uveal melanoma (UM) is the most common intraocular malignancy in adults, often leading to incurable metastatic disease. Prognosis for metastatic UM remains poor, with limited response to CTLA4 and PD1/PDL1 checkpoint inhibition. Recently, we discovered high expression of the checkpoint molecule LAG3 on CD8+ cytotoxic T-cells in metastasizing UM. We performed a clinical trial to evaluate the effect of combined PD-1 plus LAG3 inhibition in metastatic UM with correlative analyses of the immune response to therapy.
Methods We treated 27 patients. Blood samples and fine needle biopsies were collected for 26 patients. Of the currently processed 21 patient samples, correlative analyses were performed on metastatic UM biopsies (n=8) and circulating T cell samples (n=31) from patients at baseline (n=21) and the end of treatment (n=10). The tumor biopsies underwent single-cell RNA sequencing (scRNA-seq) analysis, whereas T cells underwent scRNA-seq and single cell T cell receptor sequencing (scTCR-seq).
Results Evaluating circulating T cells at baseline versus end of treatment, we identified T cell transcriptional profiles associated with therapy response, including patients with partial response (n=2), stable disease (n=7) and progressive disease (n=12). Furthermore, scTCR-seq revealed increased clonal abundance of select T cell populations following therapy. Using deep learning algorithms, we identified clonally expanded anti-melanoma circulating T-cells, which exhibited distinctive cytokine and immune checkpoint expression profiles.
Conclusions These findings indicate that T cells are capable of clonal expansion against melanoma-specific antigens in metastatic UM, and that LAG3/PD1 inhibition is associated with alterations in circulating T cells that may predict treatment response. These findings provide new insights into host immunity and response to LAG3 inhibition in metastatic UM.
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