Han Hyo S, Aldrich Amy L, Garg Saurabh K, Weinfurtner R Jared, Nguyen Jonathan V, Mo Qianxing, Whiting Junmin, Childress Jennifer, Soliman Hatem, Costa Ricardo, Armaghani Avan, Soyano Aixa, Kiluk John, Hoover Susan, Lee Marie C, Khakpour Nazanin, Shenoi Nithin, Jameel Zena, Koski Gary K, Czerniecki Brian J
Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
JAMA Oncol. 2025 Feb 1;11(2):119-127. doi: 10.1001/jamaoncol.2024.5371.
Current 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.
To 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 PARTICIPANTS: This 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.
Treatment 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.
The 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.
Twelve 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.
In 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.
ClinicalTrials.gov Identifier: NCT05325632.
目前用于ERBB2（原HER2）阳性乳腺癌患者的化疗方案会导致相当高的发病率。这些患者可能会从更有效且毒性更小的治疗中获益。
评估瘤内注射传统1型树突状细胞（cDC1）联合ERBB2靶向治疗的安全性、免疫原性和初步疗效。
设计、地点和参与者：这项1期（单中心2期试验的导入期）非随机临床试验在莫菲特癌症中心（佛罗里达州坦帕）进行。患者于2021年10月至2022年10月入组。2023年对数据进行分析。符合条件的患者为肿瘤大小为1厘米或更大的早期ERBB2阳性乳腺癌患者。
治疗包括每周6次瘤内注射cDC1，随后每周12次静脉注射80mg/m²紫杉醇。从cDC1注射第1天开始，每3周静脉注射曲妥珠单抗（8mg/kg负荷剂量，然后6mg/kg）和帕妥珠单抗（840mg负荷剂量，然后420mg），共6个周期。评估了两个剂量水平（DL）的瘤内cDC1（DL1 = 5000万个细胞，DL2 = 1亿个细胞），每个DL包括6名患者。
主要结局为安全性和免疫反应，次要结局为通过乳腺磁共振成像测量的抗肿瘤疗效以及新辅助治疗后手术时的残留癌负担。
12名ERBB2阳性患者入组并接受治疗（DL1 = 6名，DL2 = 6名）。9名患者患有激素受体阳性疾病，3名患者患有激素受体阴性疾病，临床分期为I期（n = 5）、II期（n = 4）和III期（n = 3）。cDC1最常观察到的不良事件为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，同时肿瘤内固有和适应性反应增加。免疫治疗前和免疫治疗后的乳腺磁共振成像结果显示9例客观反应，6例部分反应，3例完全反应和3例病情稳定。手术后，7名患者达到病理完全缓解。
在这项非随机临床试验中，新辅助化疗前添加瘤内cDC1和曲妥珠单抗/帕妥珠单抗耐受性良好，不良反应可控。基于安全性和免疫原性，选择DL2作为2期剂量。
ClinicalTrials.gov标识符：NCT05325632。
