在高风险局部前列腺癌患者中使用或不使用 Fc 增强型非岩藻糖基化抗 CTLA-4(BMS-986218)的新辅助雄激素剥夺疗法:随机 1 期试验

Casey R Ager, Aleksandar Obradovic, Patrick McCann, Matthew Chaimowitz, Alexander L.E. Wang, Neha Shaikh, Parin Shah, Samuel Pan, Caroline J Laplaca, Renu K Virk, Jessica C Hill, Collin Jugler, Grace DeFranco, Nilika Bhattacharya, Howard I Scher, Guarionex Joel Decastro, Christopher B Anderson, James M McKiernan, Catherine S Spina, Mark N Stein, Karie Runcie, Charles G Drake, Andrea Califano, Matthew C Dallos
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引用次数: 0

摘要

高危局部前列腺癌患者的术后复发率很高。在这些患者中,雄激素剥夺疗法(ADT)具有免疫调节作用,但调节性T细胞(Tregs)浸润的增加可能会限制ADT的抗肿瘤免疫效果。我们设计了一项新辅助临床试验,以检验BMS-986218(一种为增强抗体依赖性细胞毒性或吞噬作用(ADCC/P)而设计的新一代非岩藻糖基化抗CTLA-4抗体)是否会消耗瘤内Tregs并增强对ADT的反应。在这项单中心、双臂、开放标签研究中,24名患有高风险局部前列腺癌的男性患者被随机分配到接受单剂量ADT治疗,同时在根治性前列腺切除术前服用或不服用两剂BMS-986218(抗CTLA4-NF)。新辅助治疗的耐受性良好且可行。次要临床结果是疾病复发率,两组患者的复发率均低于预测值。从机理上讲,抗CTLA4-NF通过参与肿瘤巨噬细胞上的CD16a/FCGR3A,减少了ADT诱导的Treg积累,Treg消耗的深度与临床结果呈定量相关。瘤内树突状细胞(DC)频率的增加也与无复发有关,临床前数据表明,ADCC/P-competent抗CTLA-4抗体可引起肿瘤DC的活化和扩增。接受抗 CTLA4-NF 治疗的患者还表现出抗肿瘤 T 细胞引物增强的表型特征。总之,这项研究首次提供了针对 CTLA-4 的糖工程抗体在人体中消耗 Treg 的证据,以及它们与 ADT 联合用于高复发风险前列腺癌患者的潜力。
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Neoadjuvant androgen deprivation therapy with or without Fc-enhanced non-fucosylated anti-CTLA-4 (BMS-986218) in high risk localized prostate cancer: a randomized phase 1 trial
Men with high-risk localized prostate cancer exhibit high rates of post-surgical recurrence. In these patients, androgen deprivation therapy (ADT) is immunomodulatory, however increased infiltration of regulatory T cells (Tregs) may limit the antitumor immune effects of ADT. We designed a neoadjuvant clinical trial to test whether BMS-986218, a next-generation non-fucosylated anti-CTLA-4 antibody engineered for enhanced antibody-dependent cellular cytotoxicity or phagocytosis (ADCC/P), depletes intratumoral Tregs and augments the response to ADT. In this single-center, two-arm, open-label study, 24 men with high-risk localized prostate cancer were randomized to receive a single dose of ADT with or without two pre-operative doses of BMS-986218 (anti-CTLA4-NF) prior to radical prostatectomy. Treatment was well tolerated and feasible in the neoadjuvant setting. A secondary clinical outcome was the rate of disease recurrence, which was lower than predicted in both arms. Mechanistically, anti-CTLA4-NF reduced ADT-induced Treg accumulation through engagement of CD16a/FCGR3A on tumor macrophages, and depth of Treg depletion was quantitatively associated with clinical outcome. Increased intratumoral dendritic cell (DC) frequencies also associated with lack of recurrence, and pre-clinical data suggest ADCC/P-competent anti-CTLA-4 antibodies elicit activation and expansion of tumor DCs. Patients receiving anti-CTLA4-NF also exhibited phenotypic signatures of enhanced antitumor T cell priming. In total, this study provides the first-in-human evidence of Treg depletion by glycoengineered antibodies targeting CTLA-4 in humans and their potential in combination with ADT in prostate cancer patients with high-risk of recurrence.
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