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Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma

De Santo, Carmela; Cheng, Paul; Beggs, Andrew; Egan, Sharon; Bessudo, Albert; Mussai, Francis


Carmela De Santo

Paul Cheng

Andrew Beggs

Albert Bessudo

Francis Mussai



Metastatic melanoma is an aggressive skin cancer with a poor prognosis. Current treatment strategies for high-stage melanoma are based around the use of immunotherapy with immune checkpoint inhibitors such as anti-PDL1 or anti-CTLA4 antibodies to stimulate anti-cancer T cell responses, yet a number of patients will relapse and die of disease. Here, we report the first sustained complete remission in a patient with metastatic melanoma who failed two immunotherapy strategies, by targeting tumour arginine metabolism.

Case presentation

A 65-year-old patient with metastatic melanoma who progressed through two immunotherapy strategies with immune checkpoint inhibitor antibodies was enrolled in a phase I study (NCT02285101) and treated with 2 mg/kg intravenously, weekly pegylated recombinant arginase (BCT-100). The patient experienced no toxicities >?grade 2 and entered a complete remission which is sustained for over 30 months. RNA-sequencing identified a number of transcriptomic pathway alterations compared to control samples. The tumour had absent expression of the recycling enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC) indicating a state of arginine auxotrophy, which was reconfirmed by immunohistochemistry, and validation in a larger cohort of melanoma tumour samples.


Targeting arginine metabolism with therapeutic arginase in arginine auxotrophic melanoma can be an effective salvage for the treatment of patients who fail immunotherapy.


De Santo, C., Cheng, P., Beggs, A., Egan, S., Bessudo, A., & Mussai, F. (2018). Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma. Journal of Hematology and Oncology, 11, Article 68.

Journal Article Type Article
Acceptance Date May 2, 2018
Publication Date May 18, 2018
Deposit Date May 23, 2018
Publicly Available Date May 23, 2018
Journal Journal of Hematology and Oncology
Electronic ISSN 1756-8722
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 11
Article Number 68
Keywords Arginase; Melanoma; Immunotherapy; Metabolism; BCT-100
Public URL
Publisher URL


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