Potentiating Antitumor Efficacy Through Radiation and Sustained Intratumoral Delivery of Anti-CD40 and Anti-PDL1

• DOI: 10.1016/j.ijrobp.2020.07.2326
• Publication Date: 2020-08-05T06:10:01Z
• Authors: Hsuan-Chen Liu; Dixita I. Viswanath; Federica Pesaresi; Yitian Xu; Licheng Zhang; Nicola Di Trani; Jesus Paez-Mayorga; Nathanael Hernandez; Yu Wang; Donald R. Erm; Jeremy Ho; Antonia Susnjar; Xuewu Liu; Sandra Demaria; Shu-Hsia Chen; Bin S. Teh; Edward Brian Butler; Corrine Ying Xuan...; Alessandro Grattoni
• Keywords: Drug Implants; Mice, Inbred BALB C; 0303 health sciences; Lung Neoplasms; Liver Neoplasms; Antibodies, Monoclonal; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Injections, Intralesional; Antibodies, Monoclonal, Humanized; Combined Modality Therapy; B7-H1 Antigen; Progression-Free Survival; 12. Responsible consumption; 3. Good health; Mice; 03 medical and health sciences; Freeze Drying; Cell Line, Tumor; Animals; Female; Immunotherapy; CD40 Antigens; Injections, Intraperitoneal

Mounting evidence demonstrates that combining radiation therapy (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 was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity.We used a nanofluidic drug-eluting seed (NDES) for 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. We compared the efficacy of NDES against intraperitoneal 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.The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via 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 compared with systemic treatment. Importantly, our treatment strategy boosted the abscopal effect toward attenuating lung metastatic burden.Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via NDES, offering promise for improving therapeutic index and clinical response.