Implantable drug delivery system improves tolerability of anti-CD40/anti-PD1 and chemotherapy in a murine model of breast cancer.

Triple negative breast cancer (TNBC) is associated with the poorest prognosis among breast cancer subtypes and while immunotherapy has demonstrated some promise, its effectiveness as a monotherapy remains limited, offering only modest improvements in clinical outcomes when combined with chemotherapy. Immune checkpoint therapies, such as PD-1 inhibitors, elicit responses in a subset of patients with metastatic TNBC, and few patients experience durable effects. One reason for this limited efficacy may be due to defects in antigen presentation, as the deficiency of dendritic cells, essential for effective antigen presentation, correlates with inadequate anti-tumour immunity. To address this challenge, we report the development of a novel implantable drug delivery device that enables the localized administration of a CD40 agonist in combination with anti-PD1, doxorubicin and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). CD40 agonists are a unique class of agents that activate antigen-presenting cells, including dendritic cells and B cells, and reprogram macrophages to support anti-tumour immunity. By enabling targeted delivery to the tumour site, we aimed to enhance immune priming while mitigating systemic toxicities often observed with combinations of intravenous chemo-immunotherapy. In a 4T1 murine model of TNBC, repeated systemic administration of the therapeutic combination led to fatal xenogeneic reactions, which were not observed with the localized delivery approach. Localized delivery also slowed tumour growth compared to systemic administration of the therapeutic compounds. Immune profiling further revealed that the addition of anti-CD40 agonist antibody promoted the activation of PD-1+ CD8+ T lymphocytes within the lymph nodes in both locally and systemically treated animals. However, the localized approach achieved equivalent or enhanced immune activation without inducing the fatal immune reactions observed with systemic dosing, suggesting that localized treatment can offer a significant therapeutic advantage. This study demonstrates that our innovative localized delivery approach has the potential to significantly improve patient outcomes by maximizing efficacy and minimizing adverse effects for this aggressive subtype of breast cancer.