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http://ir.nhri.org.tw/handle/3990099045/13593
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| Title: | Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers |
| Authors: | Chang, KY;Chiang, NJ;Wu, SY;Yen, CJ;Chen, SH;Yeh, YM;Li, CF;Feng, XX;Wu, K;Johnston, A;Bomalaski, JS;Wu, BW;Gao, JJ;Subudhi, SK;Kaseb, AO;Blando, JM;Yadav, SS;Szlosarek, PW;Chen, LT |
| Contributors: | National Institute of Cancer Research |
| 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/m(2) weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab. |
| Date: | 2021-06-12 |
| Relation: | Oncoimmunology. 2021 Jun 12;10(1):Article number 1943253. |
| Link to: | http://dx.doi.org/10.1080/2162402X.2021.1943253 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2162-402X&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000672133800001 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85109791680 |
| Appears in Collections: | [陳立宗] 期刊論文
[陳尚鴻] 期刊論文
[姜乃榕] 期刊論文
[張光裕] 期刊論文
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| ISI000672133800001.pdf | | 2558Kb | Adobe PDF | 260 | View/Open |
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