PO.CT01.02 · 临床试验
瘤内微器械的I期研究揭示头颈部腺样囊性癌中不同药物处理区域间异质性的免疫和凋亡反应
Phase I study of intratumoral microdevices reveals heterogenous immune and apoptotic responses across distinct drug-treated regions in adenoid cystic carcinoma of the head and neck
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：
腺样囊性癌（ACC）是一种唾液腺或腺体癌症，常对系统治疗耐药。其罕见性和疾病异质性限制了药物反应评估，并使管理复杂化1。可植入微器械（IMD）在实体瘤中已证明具有安全性和可行性，能够实现局部药物递送，并可对每例患者平行原位评估肿瘤对多达20种治疗药物的反应2,3。本I期研究旨在评估IMD的可行性，并探索ACC对机制不同的抗癌药物的肿瘤特异性反应（NCT05553782）。
方法：
本研究招募了接受根治性手术的头颈部原发性ACC患者。植入瘤内微器械（IMD）以纳米浓度递送约15种抗癌药物，包括化疗药物、靶向药物和免疫疗法。IMD在患者肿瘤内保留三天，并在标准手术时取出。切除的肿瘤-IMD标本接受多模态分析，包括组织病理学、评估凋亡的裂解半胱天冬酶-3（CC3）免疫组化、循环免疫荧光（CycIF）和空间转录组学（ST）分析。
结果：
迄今为止，已有五名患者入组本研究。共植入14个器械（平均每名患者2.8个），中位取出量为每名患者2个IMD。仅有一名患者在大体切片过程中发生器械丢失。未观察到严重不良事件。在整个队列中，凋亡指数（CC3%）平均值最高的为ATRA（44.1%）、enfortumab vedotin（41.7%）、长春瑞滨（40.9%）、venetoclax（39.4%）和帕博利珠单抗（38.9%）；最低的为5-FU（21%）和ipilimumab（20.1%）。CycIF分析显示，ATRA、sacituzumab和enfortumab vedotin可增加CD8+细胞毒性T细胞（CD3+；CD8+，GzmB+）的浸润。用多柔比星、5-FU、卡铂和ipilimumab处理的区域显示较高的CD163表达，提示更具抑制性的髓系主导的微环境。ST揭示了药物处理区域间异质性的通路活性，包括ATRA伴免疫和凋亡相关信号增加，以及venetoclax伴p53通路上调。
结论：
IMD的植入和取出在各患者间可行且可重复。在原发性ACC中，微器械递送的ATRA、enfortumab vedotin和sacituzumab与更强的凋亡诱导效应和CD8+ T细胞富集相关，而5-FU、ipilimumab和多西他赛则表现出肿瘤相关巨噬细胞富集。这些发现可指导候选药物或联合方案的优先排序，以及治疗的个体化。
参考文献：
1.Fang等，Oral Oncol. 2022 Jul;130:105945。
2.Peruzzi等，Sci Transl Med. 2023 Sep 6;15(712):eadi0069。
3.Dominas等，IEEE Trans Biomed Eng. 2022 Jan;69(1):412-421。
查看英文原文 English abstract
Background:
Adenoid cystic carcinoma (ACC) is a salivary or glandular cancer that is frequently resistant to systemic therapies. Rarity and disease heterogeneity limit drug-response assessment and complicate management 1 . Implantable microdevices (IMD) have demonstrated safety and feasibility in solid tumors, allowing localized drug delivery and in-situ assessment of tumor responses to 20 therapeutic agents in parallel per patient 2,3 . This Phase I study aims to evaluate IMD-feasibility and explore tumor-specific responses in ACC to mechanistically distinct anticancer agents (NCT05553782).
Methods:
The study enrolled patients with primary ACC arising in the head and neck undergoing definitive surgery. Intratumoral microdevices (IMDs) were implanted to deliver ~15 anticancer drugs at nanoconcentrations, including chemotherapeutics, targeted agents, and immunotherapies. The IMDs remained in the patients' tumors for three days and were retrieved at standard surgery. Resected tumor-IMD specimens underwent multimodal analysis, including histopathology, cleaved caspase-3 (CC3) immunohistochemistry to assess apoptosis, cyclic immunofluorescence (CycIF), and spatial transcriptomic (ST) profiling.
Results:
To date, five patients have been enrolled to the study. A total of 14 devices (average 2.8 per patient) were implanted with a median retrieval of 2 IMDs/patients. Device loss occurred in only one patient during gross sectioning. No serious adverse events were observed. Across the cohort, apoptotic index (CC3%) had the highest average with ATRA (44.1%), enfortumab vedotin (41.7%), vinorelbine (40.9%), venetoclax (39.4%), and pembrolizumab (38.9%); lowest with 5-FU (21%), and ipilimumab (20.1%). CycIF analysis revealed increased infiltration of CD8 + cytotoxic T cells (CD3 + ; CD8 + , GzmB + ) with ATRA, sacitizumab and enfortumab vedotin. Regions treated with doxorubicin, 5-FU, carboplatin, and ipilimumab showed higher CD163 expression, suggesting a more suppressive myeloid-dominant microenvironment. ST revealed heterogeneous pathway activity across drug-treated regions, including ATRA with increased immune and apoptosis-related signaling, and p53 pathway upregulation with venetoclax.
Conclusions:
IMD implantation and retrieval were feasible and reproducible across patients. Across primary ACC, microdevice-delivered ATRA, enfortumab vedotin, and sacitizumab were associated with more robust apoptosis-inducing effect and CD8 + T cell enrichment, whereas 5-FU, ipilimumab, and docetaxel exhibited tumor-associated macrophage enrichment. These findings may guide prioritization of candidate drugs or combinations, and personalization of therapy.
References:
1.Fang et al, Oral Oncol. 2022 Jul;130:105945.
2.Peruzzi et al, Sci Transl Med. 2023 Sep 6;15(712):eadi0069.
3.Dominas et al, IEEE Trans Biomed Eng. 2022 Jan;69(1):412-421.
利益披露 Disclosure
F. Santa, None..
J. Kotler, None..
S. Chow, None..
S. K. Bhagavatula, None..
V. Y. Jo, None..
H. Roth, None..
V. Tarallo, None..
S. E. Martin, None..
E. Maloney, None..
W. Ahn, None..
G. J. Hanna, None.
O. Jonas,
Kibur Medical Consultant.