ImportanceCurrent chemotherapy regimens for patients with ERBB2 (formerly HER2)–positive breast cancer are associated with considerable morbidity. These patients may benefit from more effective and less toxic therapies.ObjectiveTo evaluate the safety, immunogenicity, and preliminary efficacy of intratumoral (IT) delivery of conventional type 1 dendritic cells (cDC1) in combination with ERBB2-targeted therapies.Design, Setting, and ParticipantsThis phase 1 (lead-in phase of a single-center phase 2 trial) nonrandomized clinical trial was conducted at Moffitt Cancer Center (Tampa, Florida). Patients were enrolled from October 2021 to October 2022. Data were analyzed in 2023 Patients with early-stage ERBB2-positive breast cancer with tumors 1 cm or larger were eligible.InterventionsTreatment included IT delivery of cDC1, 6 times weekly, followed by paclitaxel, 80 mg/m2, intravenously, 12 times weekly. Trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) were administered intravenously every 3 weeks for 6 cycles starting from day 1 of cDC1 injections. Two dose levels (DLs) of IT cDC1 (DL1 = 50 million and DL2 = 100 million cells) were evaluated, including 6 patients in each DL.Main Outcomes and MeasuresThe primary outcomes were the safety and immune response, and the secondary outcomes were the antitumor efficacy as measured by breast magnetic resonance imaging and residual cancer burden at surgery following neoadjuvant therapy.ResultsTwelve ERBB2-positive patients were enrolled and received treatment (DL1 = 6 and DL2 = 6). Nine patients had hormone receptor–positive disease and 3 had hormone receptor–negative disease, with clinical stage I (n = 5), II (n = 4), and III (n = 3). The most frequently observed adverse events with cDC1 were grade 1 to 2 chills (50%), fatigue (41.7%), headache (33%), and injection site reactions (33%). DL2 was associated with a diminished anti-ERBB2 CD4 T-helper 1 blood response with a concomitant increase in innate and adaptive responses within the tumor. Preimmunotherapy and postimmunotherapy breast magnetic resonance imaging results showed 9 objective responses, 6 partial responses, 3 complete responses, and 3 stable diseases. Following surgery, 7 patients had a pathologic complete response.Conclusions and RelevanceIn this nonrandomized clinical trial, the addition of IT cDC1 and trastuzumab/pertuzumab before neoadjuvant chemotherapy was well tolerated with manageable adverse effects. Based on safety and immunogenicity, DL2 was selected for the phase 2 dose.Trial RegistrationClinicalTrials.gov Identifier: NCT05325632

中文翻译：

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ERBB2 乳腺癌化疗前瘤内树突状细胞对肿瘤微环境的改变


重要性目前 ERBB2（以前称为 HER2）阳性乳腺癌患者的化疗方案与相当高的发病率相关。这些患者可能受益于更有效和毒性更小的疗法。目的评价常规 1 型树突状细胞 （cDC1） 瘤内 （IT） 递送联合 ERBB2 靶向治疗的安全性、免疫原性和初步疗效。设计、设置和参与者该 1 期（单中心 2 期试验的导入阶段）非随机临床试验在莫菲特癌症中心（佛罗里达州坦帕市）进行。患者于 2021 年 10 月至 2022 年 10 月入组。2023 年分析了数据肿瘤为 1 cm 或更大的早期 ERBB2 阳性乳腺癌患者符合条件。干预措施治疗包括 cDC1 的 IT 输送，每周 6 次，然后紫杉醇，80 mg/m2，静脉注射，每周 12 次。曲妥珠单抗 （8 mg/kg 负荷剂量，然后 6 mg/kg） 和帕妥珠单抗 （840 mg 负荷剂量，然后 420 mg） 从 cDC1 注射的第 1 天开始，每 3 周静脉内给药一次，共 6 个周期。评估了 IT cDC1 的两个剂量水平 （DLs） （DL1 = 5000 万和 DL2 = 1 亿个细胞），包括每个 DL 6 名患者。主要结局和措施主要结局是安全性和免疫反应，次要结局是通过乳腺磁共振成像测量的抗肿瘤疗效和新辅助治疗后手术中的残余癌症负担。结果纳入 12 例 ERBB2 阳性患者并接受治疗 （DL1 = 6 和 DL2 = 6）。9 例患者为激素受体阳性疾病，3 例为激素受体阴性疾病，临床分期为 I （n = 5） 、 II （n = 4） 和 III （n = 3）。 cDC1 最常见的不良事件是 1 至 2 级寒战 （50%）、疲劳 （41.7%）、头痛 （33%） 和注射部位反应 （33%）。DL2 与抗 ERBB2 CD4 辅助性 T 细胞 1 血液反应减弱相关，同时肿瘤内先天性和适应性反应增加。免疫治疗前和免疫治疗后乳腺磁共振成像结果显示 9 例客观缓解、6 例部分缓解、3 例完全缓解和 3 例疾病稳定。手术后，7 例患者出现病理完全缓解。结论和相关性在这项非随机临床试验中，在新辅助化疗前加入 IT cDC1 和曲妥珠单抗/帕妥珠单抗耐受性良好，不良反应可控。根据安全性和免疫原性，选择 DL2 作为 2 期剂量。试验注册临床试验。gov 标识符： NCT05325632