A randomised evaluation of low‐dose Ara‐<scp>C</scp> plus pegylated recombinant arginase <scp>BCT</scp>‐100 versus low dose Ara‐<scp>C</scp> in older unfit patients with acute myeloid leukaemia: Results from the <scp>LI</scp>‐1 trial

Mussai, Francis; Santo, Carmela De; Cheng, Paul; Thomas, Ian; Ariti, Cono; Upton, Laura; Scarpa, Ugo; Stavrou, Victoria; Sydenham, Mia; Burnett, Alan Kenneth; Knapper, Steven; Mehta, Priyanka; McMullin, Mary Frances; Copland, Mhairi; Russell, Nigel H.; Dennis, Mike

doi:10.1111/bjh.18560

Cited by 6 publications

(3 citation statements)

References 16 publications

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“…Nevertheless, the clinical implementation of treatments targeting arginine metabolism has so far been challenging. A randomized clinical trial testing low-dose cytarabine in combination with the human recombinant arginase BCT-100 versus low-dose cytarabine alone in 86 AML patients over 60 years of age found no difference in the overall and median survival between the two groups ( 77 ). Another approach is to inhibit arginase together with inducible nitric oxide synthase (iNOS).…”

Section: Aml Metabolismmentioning

confidence: 99%

Metabolic instruction of the graft-versus-leukemia immunity

Burk,

Apostolova

2024

Front. Immunol.

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Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed to cure hematological malignancies, such as acute myeloid leukemia (AML), through the graft-versus-leukemia (GVL) effect. In this immunological process, donor immune cells eliminate residual cancer cells in the patient and exert tumor control through immunosurveillance. However, GVL failure and subsequent leukemia relapse are frequent and associated with a dismal prognosis. A better understanding of the mechanisms underlying AML immune evasion is essential for developing novel therapeutic strategies to boost the GVL effect. Cellular metabolism has emerged as an essential regulator of survival and cell fate for both cancer and immune cells. Leukemia and T cells utilize specific metabolic programs, including the orchestrated use of glucose, amino acids, and fatty acids, to support their growth and function. Besides regulating cell-intrinsic processes, metabolism shapes the extracellular environment and plays an important role in cell-cell communication. This review focuses on recent advances in the understanding of how metabolism might affect the anti-leukemia immune response. First, we provide a general overview of the mechanisms of immune escape after allo-HCT and an introduction to leukemia and T cell metabolism. Further, we discuss how leukemia and myeloid cell metabolism contribute to an altered microenvironment that impairs T cell function. Next, we review the literature linking metabolic processes in AML cells with their inhibitory checkpoint ligand expression. Finally, we focus on recent findings concerning the role of systemic metabolism in sustained GVL efficacy. While the majority of evidence in the field still stems from basic and preclinical studies, we discuss translational findings and propose further avenues for bridging the gap between bench and bedside.

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Section: Aml Metabolismmentioning

confidence: 99%

Metabolic instruction of the graft-versus-leukemia immunity

Burk,

Apostolova

2024

Front. Immunol.

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“…In AML, a randomized study of low-dose cytarabine with rhArg1-PEG versus low-dose cytarabine alone was conducted for AML patients who were not suitable for intensive therapy. Although the addition of rhArg1-PEG to low-dose cytarabine was well-tolerated, it did not result in a significant difference in the overall response rate or survival between the treatment arms [ 156 ].…”

Section: Enzyme-mediated Arginine Deprivation Agents For Cancer Thera...mentioning

confidence: 99%

Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment

Chu

Lai

Yeh

2023

IJMS

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Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia metabolism, immune system regulation, and hormone biosynthesis—all of which are critical for tumor growth. These discoveries, coupled with the understanding of cancer cell metabolic reprogramming, have led to renewed interest in arginine deprivation as a new anticancer therapy. Several arginine deprivation strategies have been developed and entered clinical trials. The main principle behind these therapies is that arginine auxotrophic tumors rely on external arginine sources for growth because they carry reduced key arginine-synthesizing enzymes such as argininosuccinate synthase 1 (ASS1) in the intracellular arginine cycle. To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal.

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“…The most clinically relevant approach to targeting tumor arginine metabolism is through therapeutic arginine depletion with a recombinant enzyme. BCT-100 is a pegylated recombinant human arginase that leads to a rapid depletion of arginine in preclinical models and in clinical trials of adult solid and haematological patients (10)(11)(12)(13). In patients with adult malignancies, trials to date demonstrate a very encouraging safety profile as a single agent or in combination with chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

PARC: a phase I/II study evaluating the safety and activity of pegylated recombinant human arginase BCT-100 in relapsed/refractory cancers of children and young adults

Fenwick,

Weston,

Wheatley

et al. 2024

Front. Oncol.

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BackgroundThe survival for many children with relapsed/refractory cancers remains poor despite advances in therapies. Arginine metabolism plays a key role in the pathophysiology of a number of pediatric cancers. We report the first in child study of a recombinant human arginase, BCT-100, in children with relapsed/refractory hematological, solid or CNS cancers.ProcedurePARC was a single arm, Phase I/II, international, open label study. BCT-100 was given intravenously over one hour at weekly intervals. The Phase I section utilized a modified 3 + 3 design where escalation/de-escalation was based on both the safety profile and the complete depletion of arginine (defined as adequate arginine depletion; AAD <8μM arginine in the blood after 4 doses of BCT-100). The Phase II section was designed to further evaluate the clinical activity of BCT-100 at the pediatric RP2D determined in the Phase I section, by recruitment of patients with pediatric cancers into 4 individual groups. A primary evaluation of response was conducted at eight weeks with patients continuing to receive treatment until disease progression or unacceptable toxicity.Results49 children were recruited globally. The Phase I cohort of the trial established the Recommended Phase II Dose of 1600U/kg iv weekly in children, matching that of adults. BCT-100 was very well tolerated. No responses defined as a CR, CRi or PR were seen in any cohort within the defined 8 week primary evaluation period. However a number of these relapsed/refractory patients experienced prolonged radiological SD.ConclusionArginine depletion is a clinically safe and achievable strategy in children with cancer. The RP2D of BCT-100 in children with relapsed/refractory cancers is established at 1600U/kg intravenously weekly and can lead to sustained disease stability in this hard to treat population.Clinical trial registrationEudraCT, 2017-002762-44; ISRCTN, 21727048; and ClinicalTrials.gov, NCT03455140.

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A randomised evaluation of low‐dose Ara‐C plus pegylated recombinant arginase BCT‐100 versus low dose Ara‐C in older unfit patients with acute myeloid leukaemia: Results from the LI‐1 trial

Abstract: M. (2022). A randomised evaluation of low-dose Ara-C plus pegylated recombinant arginase BCT-100 versus low dose Ara-C in older unfit patients with acute myeloid leukaemia: Results from the LI-1 trial. British Journal of Haematology.

Cited by 6 publications

References 16 publications

Metabolic instruction of the graft-versus-leukemia immunity

Metabolic instruction of the graft-versus-leukemia immunity

Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment

PARC: a phase I/II study evaluating the safety and activity of pegylated recombinant human arginase BCT-100 in relapsed/refractory cancers of children and young adults

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