Salawu Abdulazeez, Wang Ben X, Han Ming, Geady Caryn, Heirali Alya, Berman Hal K, Pfister Thomas D, Hernando-Calvo Alberto, Al-Ezzi Esmail Mutahar, Stayner Lee-Anne, Gupta Abha A, Ayodele Olubukola, Lam Bernard, Hansen Aaron R, Spreafico Anna, Bedard Philippe L, Butler Marcus O, Avery Lisa, Coburn Bryan, Haibe-Kains Benjamin, Siu Lillian L, Abdul Razak Albiruni R
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Clin Cancer Res. 2023 Oct 13;29(20):4128-4138. doi: 10.1158/1078-0432.CCR-23-1137.
Non-inflamed (cold) tumors such as leiomyosarcoma do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis or PARP inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pretreated patients with leiomyosarcoma.
Patients were randomized to receive durvalumab 1,500 mg IV every 4 weeks with either olaparib 300 mg twice a day orally (Arm A) or cediranib 20 mg every day orally 5 days/week (Arm B) until unacceptable toxicity or disease progression. Paired tumor biopsies, serial radiologic assessments and stool collections were performed. Primary endpoints were safety and immune cell changes in the TME. Objective responses and survival were correlated with transcriptomic, radiomic, and microbiome parameters.
Among 30 heavily pretreated patients (15 on each arm), grade ≥ 3 toxicity occurred in 3 (20%) and 2 (13%) on Arms A and B, respectively. On Arm A, 1 patient achieved partial response (PR) with increase in CD8 T cells and macrophages in the TME during treatment, while 4 had stable disease (SD) ≥ 6 months. No patients on Arm B achieved PR or SD ≥ 6 months. Transcriptome analysis showed that baseline M1-macrophage and B-cell activity were associated with overall survival.
Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some patients with leiomyosarcoma. Baseline M1-macrophage and B-cell activity may identify patients with leiomyosarcoma with favorable outcomes on immunotherapy and should be further evaluated.
平滑肌肉瘤等非炎症性（冷）肿瘤无法从免疫检查点阻断（ICB）单药治疗中获益。将ICB与血管生成抑制剂或PARP抑制剂联合使用，可能通过改变肿瘤微环境（TME）中的免疫细胞组成来提高肿瘤免疫原性。DAPPER II期研究评估了基于ICB的联合治疗方案在经治平滑肌肉瘤患者中的安全性、免疫活性和临床活性。
患者被随机分组，每4周静脉注射1500 mg度伐利尤单抗，同时口服奥拉帕利300 mg，每日两次（A组），或口服西地尼布20 mg，每周5天，每日一次（B组），直至出现不可接受的毒性或疾病进展。进行配对肿瘤活检以及系列影像学评估和粪便采集。主要终点为安全性和TME中的免疫细胞变化。客观缓解率和生存率与转录组学、放射组学和微生物组参数相关。
在30例经大量治疗的患者中（每组15例），A组和B组分别有3例（20%）和2例（13%）发生≥3级毒性反应。在A组中，1例患者达到部分缓解（PR），治疗期间TME中的CD8 T细胞和巨噬细胞增加，4例患者疾病稳定（SD）≥6个月。B组中无患者达到PR或SD≥6个月。转录组分析显示，基线M1巨噬细胞和B细胞活性与总生存期相关。
度伐利尤单抗联合奥拉帕利可增加TME中的免疫细胞浸润，使部分平滑肌肉瘤患者临床获益。基线M1巨噬细胞和B细胞活性可能有助于识别免疫治疗预后良好的平滑肌肉瘤患者，应进一步评估。
