A Phase II Study of Docetaxel and Pembrolizumab plus Interleukin 12 Gene Therapy in Nonmetastatic, Anthracycline-Refractory Triple-Negative Breast Cancer (INTEGRAL)

Purpose: To evaluate the safety and efficacy of combining intratumoral IL12 gene therapy with docetaxel and pembrolizumab in high-risk patients with early-stage triple-negative breast cancer (TNBC) refractory to anthracycline-based neoadjuvant chemotherapy. Patients and Methods: In this single-arm, open-label phase II trial, patients with stages I to III TNBC and residual disease after anthracycline therapy received neoadjuvant docetaxel (100 mg/m² i.v.) and pembrolizumab (200 mg i.v.) every 3 weeks for four cycles. Intratumoral injections of adenoviral-mediated interleukin 12 (ADV/IL12) gene therapy were administered 3 days prior to cycles 2 to 4. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were safety and toxicity assessments. Correlative analyses included immune profiling and cytokine measurement. Results: Eight patients were enrolled; half received ADV/IL12 at a starting dose of 5 × 10¹¹ viral particles (VP) in 2 mL volume, injected into the breast tumor. Owing to adverse events (AE), the remaining four patients received 3 × 10¹¹ VPs. The trial was terminated early because of toxicity, with 87.5% of patients experiencing grade ≥3 AEs, including two treatment-related deaths. Only one (12.5%) patient who received a lower dose of ADV/IL12 achieved a pCR. Elevation of CCL4 levels was observed exclusively in the patient who achieved pCR. Conclusions: The combination of docetaxel, pembrolizumab, and intratumoral ADV/IL12 is associated with high systemic toxicity and minimal efficacy. These results underscore the need for cautious dose optimization and patient selection when integrating immunopotentiating cytokines into neoadjuvant regimens. Translational insights from this study inform safer design of future IL12-based strategies in immune-refractory TNBC.