Journal Article

Pilot Trial of Arginine Deprivation Plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

Holland, Aliya, Johnston, Amanda, O’Shea, Sirinya, Erinjeri, Joseph P., Mangarin, Levi, Bomalaski, John S., Kraehenbuehl, Lukas, Chekalil, Sara, Armstrong, Emma, Shoushtari, Alexander N., Merghoub, Taha, Wolchok, Jedd D., Francis, Jasmine H., Barker, Christopher A.

2022

Overview

Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) being much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aims at investigating the safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy, ADI-PEG 20. Nine patients were enrolled in this pilot study. The combination therapy was safe and tolerable with an absence of immune-related adverse events (irAE) of special interest, but with four of nine patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of the treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at the baseline in metastases.

• Publisher: MDPI AG,MDPI
• Subject: Antibodies / Arginine / Arginine deiminase / Argininosuccinate synthase / Cancer / Care and treatment / CD8 antigen / Clinical trials / Drug dosages / Drug therapy / Enzymes / Eye cancer / Gene expression / Genomes / Health aspects / Immune checkpoint / Immune system / Immunohistochemistry / Immunotherapy / Inflammation / Ipilimumab / Lymphocytes / Melanoma / Metastases / Metastasis / Mutation / Patients / PD-L1 protein / Testing / Tumor microenvironment / Tumors