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

Autor:	Chang KY; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan., Chiang NJ; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan., Wu SY; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Yen CJ; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Chen SH; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan., Yeh YM; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Li CF; Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan.; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan., Feng X; Polaris Pharmaceuticals, Inc., San Diego, California, USA., Wu K; Polaris Pharmaceuticals, Inc., San Diego, California, USA., Johnston A; Polaris Pharmaceuticals, Inc., San Diego, California, USA., Bomalaski JS; Polaris Pharmaceuticals, Inc., San Diego, California, USA., Wu BW; Polaris Pharmaceuticals, Inc., San Diego, California, USA., Gao J; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Subudhi SK; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Kaseb AO; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Blando JM; The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX USA., Yadav SS; The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX USA., Szlosarek PW; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, UK., Chen LT; Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2021 Jul 12; Vol. 10 (1), pp. 1943253. Date of Electronic Publication: 2021 Jul 12 (Print Publication: 2021).
DOI:	10.1080/2162402X.2021.1943253
Abstrakt:	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/m 2 weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab. (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)
Databáze:	MEDLINE
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