Messaggi chiave
- Si presentano i risultati di uno studio non randomizzato di fase I (lead-in di uno studio monocentrico di fase II) volto a valutare la sicurezza, l’immunogenicità e l’efficacia preliminare della somministrazione intratumorale (IT) di cellule dendritiche convenzionali di tipo 1 (cDC1) in combinazione con terapie anti-ERBB2 in pazienti con carcinoma mammario precoce HER2+ con tumori di dimensioni ≥1 cm.
- Lo studio ha incluso 6 pazienti per ciascun livello di dose (DL) testato (DL1, 50 milioni e DL2, 100 milioni di cellule). Gli eventi avversi (di grado 1 o 2) più frequentemente osservati sono stati brividi (50%), affaticamento (41,7%), mal di testa (33%) e reazioni nel sito di iniezione (33%). DL2 è stato associato a una diminuzione della risposta T-helper 1 anti-ERBB2 nel sangue periferico e a un concomitante aumento delle risposte innate e adattive all’interno del tumore. I risultati della risonanza magnetica mammaria eseguita pre- e post-trattamento hanno evidenziato 9 risposte obiettive (6 parziali e 3 complete) e 3 stabilizzazioni di malattia. Dopo la chirurgia, 7 pazienti hanno mostrato una risposta patologica completa.
- In questo studio non randomizzato, la somministrazione IT di cDC1 in aggiunta a trastuzumab/pertuzumab prima dell’avvio della chemioterapia neoadiuvante è stata ben tollerata e ha prodotto esiti favorevoli in termini di rimodellamento del microambiente immunitario e regressione tumorale. In base ai risultati di sicurezza e immunogenicità, DL2 è stato selezionato come dose per l’utilizzo nella fase II.
Abstract
Importance
- 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.
Objective
- 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; USA).
- 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.
Interventions
- 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.
Main outcomes and measures
- 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.
Results
- 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.
Conclusions and relevance
- 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.