Targeting the arginine metabolic brake enhances immunotherapy for leukaemia

Therapeutic approaches which aim to target Acute Myeloid Leukaemia through enhancement of patients’ immune responses have demonstrated limited efficacy to date, despite encouraging preclinical data. Examination of AML patients treated with azacitidine (AZA) and vorinostat (VOR) in a Phase II trial, demonstrated an increase in the expression of Cancer‐Testis Antigens (MAGE, RAGE, LAGE, SSX2 and TRAG3) on blasts and that these can be recognised by circulating antigen‐specific T cells. Although the T cells have the potential to be activated by these unmasked antigens, the low arginine microenvironment created by AML blast Arginase II activity acts a metabolic brake leading to T cell exhaustion. T cells exhibit impaired proliferation, reduced IFN‐γ release and PD‐1 up‐regulation in response to antigen stimulation under low arginine conditions. Inhibition of arginine metabolism enhanced the proliferation and cytotoxicity of anti‐NY‐ESO T cells against AZA/VOR treated AML blasts, and can boost anti‐CD33 Chimeric Antigen Receptor‐T cell cytotoxicity. Therefore, measurement of plasma arginine concentrations in combination with therapeutic targeting of arginase activity in AML blasts could be a key adjunct to immunotherapy. What's new? To date, cellular immunotherapy strategies against acute myeloid leukaemia (AML) have demonstrated limited efficacy. Here, arginine concentrations in AML patients were shown to be significantly lower than in healthy controls, both at diagnosis and during immunomodulatory treatment. Although T cells were able to recognise and be activated by antigens expressed on AML blasts, the low arginine microenvironment acted as a metabolic brake on T cell function and expansion. Targeting arginine metabolism in AML patients should be an adjunct to current treatment strategies in order to enhance host anti‐leukaemia immunity and boost the activity of CAR‐T or adoptive T cell therapies.