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

Abstract

Background

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.

Conclusions

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

Citation

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. https://doi.org/10.1186/s13045-018-0612-6

• 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
• DOI: https://doi.org/10.1186/s13045-018-0612-6
• Keywords: Arginase; Melanoma; Immunotherapy; Metabolism; BCT-100
• Public URL: https://nottingham-repository.worktribe.com/output/932822
• Publisher URL: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-018-0612-6
• Contract Date: May 23, 2018