Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor.
Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor.
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DOI：
10.1136/jitc-2021-002371
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发表时间：
2021-04
影响因子：
10.9
通讯作者：
Redmond WL
中科院分区：
文献类型：
--
作者：
Curti BD;Koguchi Y;Leidner RS;Rolig AS;Sturgill ER;Sun Z;Wu Y;Rajamanickam V;Bernard B;Hilgart-Martiszus I;Fountain CB;Morris G;Iwamoto N;Shimada T;Chang S;Traber PG;Zomer E;Horton JR;Shlevin H;Redmond WL
PD-1/PD-L1接合和半乳糖凝集素-3（Gal-3）的过表达是肿瘤诱导的免疫抑制的关键机制，有助于免疫治疗耐药性。我们假设用贝拉克丁（GR-MD-02）加抗PD-1（派姆单抗）阻断Gal-3将增强转移性黑色素瘤（MM）和头颈部鳞状细胞癌（HNSCC）患者的肿瘤缓解。我们在晚期MM或HNSCC患者中进行了Belapectin+Pembrolizumab的I期剂量递增研究（NCT 02575404）。在帕博利珠单抗之前60分钟以2、4或8 mg/kg IV施用贝拉克丁（200 mg IV，每3周一次，持续5个周期）。缓解患者继续pembrolizumab单药治疗长达17个周期。主要合格性要求是东部肿瘤协作组功能状态为0-2，可测量或可评估的疾病，并且没有活动性自身免疫性疾病。允许既往接受T细胞检查点抗体治疗。在50%的MM（7/14）和33%的HNSCC（2/6）患者中观察到客观缓解。Belapectin+pembrolizumab与pembrolizumab单药治疗的预期免疫介导的不良事件相关。在研究的剂量范围内，贝拉克丁无剂量限制性毒性。与无应答者相比，在应答者中观察到效应记忆T细胞活化显著增加，单核细胞骨髓源性抑制细胞（M-MDSC）减少。外周中Gal-3+肿瘤细胞和PD-1+ CD 8 + T细胞的基线表达增加与缓解相关，帕博利珠单抗的血清谷水平较高也是如此。Belapectin+Pembrolizumab治疗在MM和HNSCC中具有活性。Gal-3表达增加、效应记忆T细胞扩增和M-MDSC减少与临床应答相关。计划进行进一步调查。
PD-1/PD-L1 engagement and overexpression of galectin-3 (Gal-3) are critical mechanisms of tumor-induced immune suppression that contribute to immunotherapy resistance. We hypothesized that Gal-3 blockade with belapectin (GR-MD-02) plus anti-PD-1 (pembrolizumab) would enhance tumor response in patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). We performed a phase I dose escalation study of belapectin+pembrolizumab in patients with advanced MM or HNSCC (NCT02575404). Belapectin was administered at 2, 4, or 8 mg/kg IV 60 min before pembrolizumab (200 mg IV every 3 weeks for five cycles). Responding patients continued pembrolizumab monotherapy for up to 17 cycles. Main eligibility requirements were a functional Eastern Cooperative Oncology Group status of 0–2, measurable or assessable disease, and no active autoimmune disease. Prior T-cell checkpoint antibody therapy was permitted. Objective response was observed in 50% of MM (7/14) and and 33% of HNSCC (2/6) patients. Belapectin+pembrolizumab was associated with fewer immune-mediated adverse events than anticipated with pembrolizumab monotherapy. There were no dose-limiting toxicities for belapectin within the dose range investigated. Significantly increased effector memory T-cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) were observed in responders compared with non-responders. Increased baseline expression of Gal-3+ tumor cells and PD-1+CD8+ T cells in the periphery correlated with response as did higher serum trough levels of pembrolizumab. Belapectin+pembrolizumab therapy has activity in MM and HNSCC. Increased Gal-3 expression, expansion of effector memory T cells, and decreased M-MDSCs correlated with clinical response. Further investigation is planned.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
82.9
作者：
Fairfax BP;Taylor CA;Watson RA;Nassiri I;Danielli S;Fang H;Mahé EA;Cooper R;Woodcock V;Traill Z;Al-Mossawi MH;Knight JC;Klenerman P;Payne M;Middleton MR
通讯作者：
Middleton MR
影响因子：
8.4
作者：
Basak, Edwin A.;Koolen, Stijn L. W.;Mathijssen, Ron H. J.
通讯作者：
Mathijssen, Ron H. J.
影响因子：
4.4
作者：
Baecher-Allan, Clare;Wolf, Elizabeth;Haller, David A.
通讯作者：
Haller, David A.
影响因子：
50.3
作者：
Gide, Tuba N.;Quek, Camelia;Wilmott, James S.
通讯作者：
Wilmott, James S.