Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers

Kwang Yu Chang, Nai Jung Chiang, Shang Yin Wu, Chia Jui Yen, Shang Hung Chen, Yu Min Yeh, Chien Feng Li, Xiaoxing Feng, Katherine Wu, Amanda Johnston, John S. Bomalaski, Bor Wen Wu, Jianjun Gao, Sumit K. Subudhi, Ahmed O. Kaseb, Jorge M. Blando, Shalini S. Yadav, Peter W. Szlosarek, Li Tzong Chen

研究成果: Article同行評審

22 引文 斯高帕斯(Scopus)

摘要

Background: Pegylated arginine deiminase (ADI-PEG 20) is a metabolism-based strategy that depletes arginine, resulting in tumoral stress and cytotoxicity. Preclinically, ADI-PEG 20 modulates T-cell activity and enhances the therapeutic efficacy of programmed death-1 (PD-1) inhibition. Methods: A phase 1b study, including a dose-escalation cohort and an expansion cohort, was undertaken to explore the effects of ADI-PEG 20 in combination with pembrolizumab, an anti-PD-1 antibody, for safety, pharmacodynamics, and response. CD3 levels and programmed death-ligand 1 (PD-L1) expression were assessed in paired biopsies collected prior to and after ADI-PEG 20 treatment but before pembrolizumab. Results: Twenty-five patients, nine in the dose-escalation cohort and sixteen in the expansion cohort, were recruited. Treatment was feasible with adverse events consistent with those known for each agent, except for Grade 3/4 neutropenia which was higher than expected, occurring in 10/25 (40%) patients. Mean arginine levels were suppressed for 1–3 weeks, but increased gradually. CD3+ T cells increased in 10/12 (83.3%) subjects following ADI-PEG 20 treatment, including in three partial responders (p = .02). PD-L1 expression was low and increased in 3/10 (30%) of subjects. Partial responses occurred in 6/25 (24%) heavily pretreated patients, in both argininosuccinate synthetase 1 proficient and deficient subjects. Conclusions: The immunometabolic combination was safe with the caveat that the incidence of neutropenia might be increased compared with either agent alone. ADI-PEG 20 treatment increased T cell infiltration in the low PD-L1 tumor microenvironment. The recommended phase 2 doses are 36 mg/m2 weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab.

原文English
文章編號1943253
期刊OncoImmunology
10
發行號1
DOIs
出版狀態Published - 2021

All Science Journal Classification (ASJC) codes

  • 免疫學和過敏
  • 免疫學
  • 腫瘤科

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