PEG-arginase and complete remission in immunotherapy-resistant melanoma, a case study

While the relatively recently approved treatment options for melanoma (both targeted and immunotherapy) have been absolutely life saving for many, myself included, there are still far too many of us in need of something else!!!  To that end, here is a case study...

To begin, PEG is polyethylene glycol, a vehicle used to make things soluble in water (or the human body) so that a drug/substance can be administered.  It is use in PEG-interferon, for example.  Arginase is an enzyme that breaks down arginine.  Arginine is an essential amino acid needed for protein synthesis.  It is used in the liver, for example, to help excrete ammonia.  Strangely, some melanoma cells are unable to synthesize their own arginine, making them dependent on arginine from other cells.  So now...there is this:

Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma.  De Santo, Cheng, Beggs, et al. J Hematol Oncol. 2018 May 18.

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.

For what it's worth! - c