Szlosarek Peter W, Phillips Melissa M, Pavlyk Iuliia, Steele Jeremy, Shamash Jonathan, Spicer James, Kumar Sanjeev, Pacey Simon, Feng Xiaoxing, Johnston Amanda, Bomalaski John, Moir Graeme, Lau Kelvin, Ellis Stephen, Sheaff Michael
Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-A Cancer Research UK Center of Excellence, Queen Mary University of London, London, United Kingdom.
Department of Medical Oncology, Barts Health NHS Trust, St Bartholomew's Hospital, London, United Kingdom.
JTO Clin Res Rep. 2020 Sep 3;1(4):100093. doi: 10.1016/j.jtocrr.2020.100093. eCollection 2020 Nov.
Pegargiminase (ADI-PEG 20; ADI) degrades arginine and potentiates pemetrexed (Pem) cytotoxicity in argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). We conducted a phase 1 dose-expansion study at the recommended phase 2 dose of ADI-PEG 20 with Pem and cisplatin (ADIPemCis), to further evaluate arginine-lowering therapy in ASS1-deficient MPM and explore the mechanisms of resistance.
A total of 32 patients with ASS1-deficient MPM (11 epithelioid; 10 biphasic;11 sarcomatoid) who were chemonaive received weekly intramuscular pegargiminase (36 mg/m) with Pem (500 mg/m) and cisplatin (75 mg/m) intravenously, every 3 weeks (six cycles maximum). Maintenance pegargiminase was permitted until disease progression or withdrawal. Safety, pharmacodynamics, immunogenicity, and efficacy were determined. Biopsies were performed in progressing patients to explore the mechanisms of resistance to pegargiminase.
The treatment was well tolerated. Most adverse events were of grade 1/2, whereas four nonhematologic grade 3/4 adverse events related to pegargiminase were reversible. Plasma arginine decreased whereas citrulline increased; this was maintained by 18 weeks of ADIPemCis therapy. The disease control rate in 31 assessed patients was 93.5% (n = 29 of 31; 95% confidence interval [CI]: 78.6%-99.2%), with a partial response rate of 35.5% (n = 11 of 31; 95% CI: 19.2%-54.6%). The median progression-free and overall survivals were 5.6 (95% CI: 4.0-6.0) and 10.1 (95% CI: 6.1-11.1) months, respectively. Progression biopsies on pegargiminase revealed a statistically significant influx of macrophages (n = 6; = 0.0255) and patchy tumoral ASS1 reexpression (n = 2 of 6). In addition, we observed increased tumoral programmed death-ligand 1-an ADI-PEG 20 inducible gene-and the formation of CD3-positive T lymphocyte aggregates on disease progression (n = 2 of 5).
The dose expansion of ADIPemCis confirmed the high clinical activity and good tolerability in ASS1-deficient poor-prognosis mesothelioma, underpinning an ongoing phase 3 study (ClinicalTrials.govNCT02709512). Notably, resistance to pegargiminase correlated with marked macrophage recruitment and-along with the tumor immune microenvironment-warrants further study to optimize arginine deprivation for the treatment of mesothelioma.
培加吉酶（ADI-PEG 20；ADI）可降解精氨酸，并增强培美曲塞（Pem）对精氨酸琥珀酸合成酶1（ASS1）缺陷型恶性胸膜间皮瘤（MPM）的细胞毒性。我们以培加吉酶-培美曲塞-顺铂（ADIPemCis）的推荐2期剂量开展了1期剂量扩展研究，以进一步评估ASS1缺陷型MPM中的精氨酸降低疗法，并探索耐药机制。
32例未经化疗的ASS1缺陷型MPM患者（11例上皮样；10例双向型；11例肉瘤样），每周接受一次肌肉注射培加吉酶（36mg/m²），并每3周静脉注射一次培美曲塞（500mg/m²）和顺铂（75mg/m²）（最多六个周期）。允许持续使用培加吉酶直至疾病进展或停药。测定安全性、药效学、免疫原性和疗效。对病情进展的患者进行活检，以探索对培加吉酶的耐药机制。
该治疗耐受性良好。大多数不良事件为1/2级，而4例与培加吉酶相关的非血液学3/4级不良事件是可逆的。血浆精氨酸降低而瓜氨酸增加；ADIPemCis治疗18周时维持这种变化。31例评估患者的疾病控制率为93.5%（31例中的29例；95%置信区间[CI]：78.6%-99.2%），部分缓解率为35.5%（31例中的11例；95%CI：19.2%-54.6%）。无进展生存期和总生存期的中位数分别为5.6（95%CI：4.0-6.0）个月和10.1（95%CI：6.1-11.1）个月。对培加吉酶治疗后病情进展的患者进行活检显示，巨噬细胞大量涌入具有统计学意义（n=6；P=0.0255），且6例中有2例肿瘤ASS1呈斑片状重新表达。此外，我们观察到疾病进展时肿瘤程序性死亡配体1（一种ADI-PEG 20诱导基因）增加，以及CD3阳性T淋巴细胞聚集形成（5例中有2例）。
ADIPemCis的剂量扩展证实了其在ASS1缺陷型预后不良的间皮瘤中具有高临床活性和良好耐受性，这为正在进行的3期研究（ClinicalTrials.govNCT02709512）提供了支持。值得注意的是，对培加吉酶的耐药与巨噬细胞的显著募集相关，并且与肿瘤免疫微环境一起，有待进一步研究以优化精氨酸剥夺用于间皮瘤的治疗。
