@article{74a21ef4fe9f4c23a2b4c35b5d65e78f,
title = "Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers",
abstract = "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.",
author = "Chang, {Kwang Yu} and Chiang, {Nai Jung} and Wu, {Shang Yin} and Yen, {Chia Jui} and Chen, {Shang Hung} and Yeh, {Yu Min} and Li, {Chien Feng} and Xiaoxing Feng and Katherine Wu and Amanda Johnston and Bomalaski, {John S.} and Wu, {Bor Wen} and Jianjun Gao and Subudhi, {Sumit K.} and Kaseb, {Ahmed O.} and Blando, {Jorge M.} and Yadav, {Shalini S.} and Szlosarek, {Peter W.} and Chen, {Li Tzong}",
note = "Funding Information: K-Y.C. reports non-financial support from Polaris Pharmaceuticals, personal fees from MSD, outside the submitted work; S-Y.W. reports personal fees and non-financial support from Novartis, personal fees from Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Merck KGaA, outside the submitted work; C-F.L. reports grants from Polaris, outside the submitted work; X.F. reports personal fees from Polaris Pharmaceuticals, outside the submitted work; A.J. reports personal fees from Polaris Pharmaceuticals, during the conduct of the study; personal fees from Polaris Pharmaceuticals, outside the submitted work; J.S.B. reports other from Polaris Pharmaceuticals, Inc., during the conduct of the study; in addition, J.S.B. has a patent Methods of treatment with arginine deiminase issued. P.W.S. reports grants from Polaris Group, personal fees from BMS, non-financial support from Merck, during the conduct of the study; J.G. reports personal fees from ARMO Biosciences, AstraZeneca, CRISPR Therapeutics, Jounce, NEKTAR, Pfizer, Janssen, Polaris, Symphogen, outside the submitted work; S.K.S. reports personal fees and other from Janssen Oncology, Apricity Health, AstraZeneca, Bristol-Myers Squibb, personal fees from Polaris, Dendreon, Amgen, Bayer, Dava Oncology, Cancer Now, MEDACorp, Parker Institute for Cancer Immunotherapy, Society for Immunotherapy of Cancer, outside the submitted work; L-T.C. reports grants from Polaris, during the conduct of the study; personal fees from MSD, outside the submitted work; N-J.C., C-J.Y., S-H.C., Y-M.Y., K.W., B-W.W., A.O.K., J.M.B., S.S.Y. have nothing to disclose. Funding Information: Polaris Pharmaceuticals provided the study drug and worked with investigators on the trial design and plan, collection and analysis of data, and interpretation of results. The study was funded by Polaris Pharmaceuticals. The authors express sincere appreciation to all participants in this clinical trial and to their families. We acknowledge all the effort from clinical investigators, statisticians, clinical research associates, and administrative staff who have contributed to the trial. Publisher Copyright: {\textcopyright} 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.",
year = "2021",
doi = "10.1080/2162402X.2021.1943253",
language = "English",
volume = "10",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",
number = "1",
}