Combining radiotherapy with localized immunotherapy via implantable nanochannel platform in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is one of the most aggressive and lethal subtype of breast cancer (BC) and it covers 15-20% of overall BC diagnoses. While effective targetable therapy has been developed for subtypes expressing the estrogen, progesterone or Her2Neu receptors, TNBC lack these therapeutic targets. Thus, TNBC patients suffer from a dismal clinical prognosis associated with high metastatic burden. Therefore, there is an urgent clinical need to develop effective treatments for combating TNBC. Over the last decade, immunotherapy has become increasingly impactful owing to development of several promising combinational strategies for cancer treatment. Many experimental evidence suggest that the combination of immunotherapy with radiotherapy (RT) is a rational strategy for hard-to-treat cancers as it induces a substantive immunogenic effect, necessary to reprogram the tumor immune microenvironment. However, the pursuit of effective and durable cancer treatment remains challenging, because conventional systemic administration of immunotherapeutics leads to toxicities and off-target adverse effects, which are treatment limiting. Evidently, there’s a critical clinical demand to develop an effective immunotherapeutics delivery approach to improve outcome while attenuating adverse effects: to fulfill this need we have previously developed a minimally invasive device called the nanofluidic drug-eluting seed (NDES) for targeted local immunotherapy delivery. Implanted intratumorally, the NDES harnesses a nanochannel membrane to passively control rate of drug diffusion to achieve constant and local release of immunotherapeutics. The project specific aim was to evaluate NDES-mediated intratumoral delivery of monoclonal antibodies, anti-CD40 and anti-PD-L1, in conjunction with radiotherapy for TNBC treatment. The efficacy on tumor control and toxicity effects of this innovative strategy were assessed in comparison to intraperitoneal systemic administration. To analyze also local and systemic anti-tumor immune response imaging mass cytometry and flow cytometry were performed. We demonstrate that the combination of RT and sustained intratumoral release of CD40 and PDL1 via the NDES improves both the local and systemic immune response translating into significant tumor burden reduction and mitigation of toxicity assessed via physiologic and pathologic conditions. Crucially, the results show that this strategy can boost the abscopal effect and attenuate lung metastatic burden. Overall, we demonstrate that the combination of immunotherapy via the NDES and RT improves immune-mediated tumor control and minimizes toxicity, offering an emerging strategy for combating TNBC.