Efficient drug delivery to lymph nodes by intradermal administration and enhancement of anti-tumor effects of immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors are novel immunotherapy drugs that have improved cancer treatments. Yet only a small percentage of patients experience durable responses to immune checkpoint inhibitors. Recently, it has been suggested that lymph nodes are important for the efficacy of immunotherapy. However, it is still unclear whether the efficient anti-PD-L1 antibody delivery to tumor-draining lymph nodes improves drug efficacy. In this study, we first characterized lymphatic drug delivery by intradermal administration compared with conventional subcutaneous and systemic administration in rodents and non-human primates. The results confirmed that intradermal administration of immune checkpoint inhibitors is suitable for efficient delivery to the tumor-draining lymph node. In FM3A and EMT6 tumor mice models with different PD-L1 expressions in tumor, efficient delivery of anti-PD-L1 antibody to tumor-draining lymph node by intradermal administration resulted in efficient inhibition of tumor growth in both models. The intradermal administration of low-dose anti-PD-L1 antibody also significantly suppressed tumor growth compared to intraperitoneal administration. It also suppressed tumor growth regardless of PD-L1 expression in tumors, suggesting the importance of blocking PD-L1 in tumor-draining lymph nodes. Hence, efficient delivery by intradermal administration of anti-PD-L1 antibody to tumor-draining lymph node might to be helpful to enhance drug efficacy and potentially reduce adverse events.