Potentiating anti-tumor efficacy through radiation and sustained intratumoral delivery of anti-CD40 and anti-PDL1.

Abstract Purpose Mounting evidence demonstrates that combining radiotherapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study is to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity. Methods We utilized a nanofluidic drug-eluting seed (NDES) for the sustained intratumoral delivery of combinational antibodies, CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer (TNBC). We compared the efficacy of NDES against intraperitoneal (IP) administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively. Results The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via the NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation when compared to systemic treatment. Importantly, our treatment strategy boosted the abscopal effect towards attenuating lung metastatic burden. Conclusions Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via the NDES, offering promise for improving therapeutic index and clinical response.