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

Autor: Kraehenbuehl L; Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Holland A; Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Armstrong E; Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., O'Shea S; Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Mangarin L; Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Chekalil S; Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Johnston A; Polaris Pharmaceuticals, Inc., San Diego, CA 92121, USA., Bomalaski JS; Polaris Pharmaceuticals, Inc., San Diego, CA 92121, USA., Erinjeri JP; Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Barker CA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Francis JH; Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Wolchok JD; Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.; Weill Cornell Medical College; New York, NY 10065, USA., Merghoub T; Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.; Weill Cornell Medical College; New York, NY 10065, USA., Shoushtari AN; Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.; Weill Cornell Medical College; New York, NY 10065, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 May 26; Vol. 14 (11). Date of Electronic Publication: 2022 May 26.
DOI: 10.3390/cancers14112638
Abstrakt: 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.
Databáze: MEDLINE
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