Intratumoral dendritic cell (DC1) therapy prior to neoadjuvant chemotherapy in HER2-positive breast cancer (NATASHA trial).

2594 Background: Enhancing the efficacy of neoadjuvant therapy (NAT) while minimizing treatment-related toxicity remains a critical unmet need for patients (pts) with HER2-positive (HER2+) breast cancer (BC). We previously reported intratumoral (IT) delivery of increasing doses (50 million and 100 million cells) of conventional type I dendritic cells (DC1) combined with anti-HER2 antibodies is safe and effective in altering the tumor microenvironment (TME) and inducing tumor regression in early-stage HER2+ BC. We conducted a phase II neoadjuvant clinical trial of IT DC1 (NCT05325632). Methods: Pts with early-stage HER2+ BC with tumor ≥ 1cm were eligible. Treatment included initial immunotherapy with IT DC1 weekly x6 (100 million) followed by paclitaxel 80 mg/m 2 IV weekly x12. Starting from day 1, pts also received trastuzumab (H) IV (8 mg/kg loading dose, then 6 mg/m 2 ) and pertuzumab (P) IV (840 mg loading dose, then 420 mg) every 3 weeks x 6 cycles. Core needle biopsies were obtained at baseline and at week 6 following the last DC1 injection and analyzed by multiplex immunofluorescence (mIF) to assess immune cell infiltration. At these timepoints and post-chemotherapy, radiologic response was assessed by breast MRI and blood was collected for biomarker and ctDNA analysis using a personalized, tumor-informed test (Signatera, Natera, Inc.). The primary end point of this study is pathologic complete response rate (pCR). Results: A total of 47 pts (24 HR+/HER2+, 23 HR-/HER2+) were enrolled between 5/2022 and 10/2025. Median age was 54 years (range 27-82). 21 pts had biopsy-proven axillary node positive disease with clinical stage I/II/III (7/30/10). All pts completed NAT, and 42 pts underwent surgery as of 1/22/2026. The pCR rates for HR+/HER2+ and HR-/HER2+ were 50% (12/24) and 89% (16/18), respectively. The most frequent toxicities related to DC1 were grade 1/2 chills, flu-like symptoms, headache, nausea, fever, and injection site reaction. IT DC1 + HP therapy was associated with a significant increase in intratumoral CD3⁺ T cell infiltration and a decrease in tumor cells assessed by mIF. ctDNA levels were evaluable for 25 patients (13 HR+ and 12 HR-). Sixteen pts (64%) had positive ctDNA (6 HR+ and 10 HR-) at baseline and 14/16 cleared ctDNA with NAT (13/16 cleared ctDNA post- IT DC1+HP, prior to chemotherapy). At present (median post-surgery follow-up: 15.1 mos.; median follow-up from last ctDNA test: 8.7 mos.), no pts have experienced disease recurrence. Conclusions: IT DC1 + HP prior to neoadjuvant paclitaxel + HP in HER2+ BC pts was well tolerated with manageable toxicities. IT DC1 led to immune cell infiltration and ctDNA clearance with improved pathologic tumor response rates, particularly in HR-/HER2+ BC. Updated surgical outcomes and biomarker results (mIF, MRI and ctDNA) will be presented at the meeting. Clinical trial information: NCT05325632 .