肿瘤细胞治疗研究
英文原题：Phase 1/2 study of monalizumab plus durvalumab in patients with advanced solid tumors.
尽管疗效有限，monalizumab联合durvalumab耐受性良好，且在外周血和TME中观察到了令人鼓舞的免疫激活。
monalizumab（抗NKG2A/CD94）与durvalumab（抗程序性死亡配体-1）联合可通过靶向固有免疫和适应性免疫促进抗肿瘤免疫。这项monalizumab与durvalumab的1/2期研究评估了其在晚期实体瘤患者中的安全性、抗肿瘤活性和药效学。主体：入组患者为18岁及以上、未接受过免疫治疗、患有晚期疾病、Eastern Cooperative Oncology Group体能状态为0-1，并且在复发/转移背景下接受过1-3线系统性治疗。在第1部分（剂量递增）中，患者接受durvalumab 1500 mg每4周一次（Q4W）联合递增剂量的monalizumab每2周一次/每4周一次（n=15）。第1部分中的剂量扩展包括宫颈癌患者（n=15；durvalumab 1500 mg Q4W和monalizumab 750 mg每2周一次）或转移性微卫星稳定（MSS）-结直肠癌（CRC）患者（n=15；durvalumab 1500 mg Q4W和monalizumab 750 mg Q4W）。在第2部分（剂量扩展）中，MSS-CRC（n=40）、非小细胞肺癌（NSCLC；n=20）、MSS-子宫内膜癌（n=40）或卵巢癌（n=40）患者接受durvalumab 1500 mg Q4W和monalizumab 750 mg每2周一次。主要终点为安全性。次要终点包括根据Response Evaluation Criteria In Solid Tumors version 1.1（RECIST v1.1）评估的抗肿瘤活性。探索性分析包括评估外周血和肿瘤微环境（TME）中T细胞和自然杀伤（NK）细胞的活化与增殖。该研究共入组185例患者（第1部分45例；第2部分140例）。未观察到剂量限制性毒性，且未达到最大耐受剂量。在第2部分中，最常见的治疗相关不良事件为疲乏（12.1%）、乏力（9.3%）、腹泻（9.3%）、瘙痒（7.9%）和发热（7.1%）。在扩展队列中，缓解率分别为0%（宫颈癌）、7.7%（MSS-CRC）、10%（NSCLC）、5.4%（卵巢癌）和0%（MSS-子宫内膜癌）。观察到持续的NK细胞活化、CD8+ T细胞增殖、血清CXCL10（C-X-C基序趋化因子配体10）和CXCL11水平升高，以及CD8+和颗粒酶B+细胞对肿瘤的浸润增加。
BACKGROUND: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors. MAIN BODY: Immunotherapy-na ve patients aged 18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8 + T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8 + and granzyme B + cells were observed. CONCLUSIONS: Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME. TRIAL REGISTRATION NUMBER: NCT02671435.
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