Adams Sylvia, Demaria Sandra, Rinchai Darawan, Wang Ena, Novik Yelena, Oratz Ruth, Fenton-Kerimian Maria, Levine Pascale G, Li Xiaochun, Marincola Francesco, Jin Ping, Stroncek David, Goldberg Judith, Bedognetti Davide, Formenti Silvia Chiara
Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA.
Department of Radiation Oncology, Weill Cornell Medicine, New York, New York, USA.
J Immunother Cancer. 2025 Apr 5;13(4):e011173. doi: 10.1136/jitc-2024-011173.
Toll-like receptor (TLR) agonists and radiation therapy hold promise for cancer immunotherapy. We conducted a phase I/II trial combining topical imiquimod (IMQ, a TLR-7 agonist) and local radiotherapy (RT) in patients with metastatic breast cancer accompanied by longitudinal transcriptional analysis of tumor biopsies.
The primary objective of the trial (NCT01421017) was to assess systemic responses by immune-related response criteria (irRC) after an 8-week cycle of topical IMQ and concurrent local RT (cohort 1). An amendment to the trial added two cohorts, both received one dose of cyclophosphamide (CTX) administered 1 week before study treatment initiation, IMQ/RT/CTX (cohort 2) and RT/CTX control (cohort 3). Cutaneous metastases were prospectively assigned to treatment with IMQ and RT (area A) or IMQ alone (area B). Secondary objectives were safety (Common Terminology Criteria for Adverse Events criteria) and local response in skin metastases. In all IMQ cohorts, tumors were biopsied before treatment and at 2 and 3 weeks.
31 patients were enrolled (n=12, n=12, and n=7, in cohort 1, 2, and 3, respectively), with 4 out of 24 patients in the IMQ cohorts showing systemic tumor responses (two complete responses (CR) and two partial responses (PR)). No objective responses were observed in the seven patients enrolled in the control arm (RT alone). The treatment was well-tolerated, no grade 4-5 treatment-related adverse events occurred and grade 3 AEs were manageable (anemia, local pain, and local ulceration, n=1 each). Local objective responses were observed in 19/24 (9 CR and 10 PR) and 5/24 (5 PR) in areas treated with combined IMQ-RT and IMQ alone, respectively (p<0.001). All 24 patients treated with IMQ underwent serial biopsies, and 84 samples yielded sufficient material for transcriptional analyses. These revealed that the presence of a T-helper 1 functional orientation of the tumor microenvironment paralleled by the downregulation of DNA-repair genes was associated with CR after IMQ+RT, but not after IMQ alone. No post-treatment activation of immune-effector functions was observed in stable and progressing lesions.
Our findings support the safety and clinical efficacy of combining topical IMQ with local RT for recurrent breast cancer, with evidence of local and occasional systemic antitumor activity.
NCT01421017.
Toll样受体（TLR）激动剂和放射治疗在癌症免疫治疗方面具有前景。我们开展了一项I/II期试验，将局部使用咪喹莫特（IMQ，一种TLR-7激动剂）与局部放疗（RT）相结合，用于治疗转移性乳腺癌患者，并对肿瘤活检进行纵向转录分析。
该试验（NCT01421017）的主要目标是根据免疫相关反应标准（irRC）评估在为期8周的局部IMQ与同期局部RT周期（队列1）后的全身反应。试验修正案增加了两个队列，均在研究治疗开始前1周接受一剂环磷酰胺（CTX），即IMQ/RT/CTX（队列2）和RT/CTX对照（队列3）。皮肤转移灶被前瞻性地分配接受IMQ和RT治疗（A区）或仅接受IMQ治疗（B区）。次要目标是安全性（不良事件通用术语标准）和皮肤转移灶的局部反应。在所有IMQ队列中，治疗前以及治疗后2周和3周对肿瘤进行活检。
共纳入31例患者（队列1、2、3分别为12例、12例和7例），IMQ队列中的24例患者中有4例出现全身肿瘤反应（2例完全缓解（CR）和2例部分缓解（PR））。在仅接受放疗的7例对照臂患者中未观察到客观反应。该治疗耐受性良好，未发生4-5级治疗相关不良事件，3级不良事件可控制（贫血、局部疼痛和局部溃疡，各1例）。在联合使用IMQ-RT和仅使用IMQ治疗的区域，分别观察到19/24（9例CR和10例PR）和5/24（5例PR）的局部客观反应（p<0.001）。所有接受IMQ治疗的24例患者均接受了系列活检，84份样本产生了足够用于转录分析的材料。这些结果显示，肿瘤微环境存在T辅助1功能方向且DNA修复基因下调与IMQ+RT后的CR相关，但仅使用IMQ后则不然。在稳定和进展性病变中未观察到治疗后免疫效应功能的激活。
我们的研究结果支持局部使用IMQ与局部RT联合用于复发性乳腺癌的安全性和临床疗效，有局部和偶尔的全身抗肿瘤活性的证据。
NCT01421017。
