Synergistic Transcutaneous Immunotherapy Enhances Antitumor Immune Responses through Delivery of Checkpoint Inhibitors

TLDR

Immunotherapy’s clinical benefit is limited by poor lymphocyte infiltration and off‑target adverse events. The authors developed a microneedle‑based transcutaneous system that locally targets PD‑1 and IDO for melanoma treatment. A hyaluronic‑acid nanocapsule carrying anti‑PD‑1 and the IDO inhibitor 1‑MT delivers sustained release and enhanced retention of checkpoint inhibitors in the tumor microenvironment. In B16F10 melanoma mice, the synergistic therapy produced strong antitumor activity, boosted effective T‑cell immunity, and reduced local immunosuppression.

Abstract

Despite the promising efficacy of immunoregulation in cancer therapy, the clinical benefit has been restricted by inefficient infiltration of lymphocytes in the evolution of immune evasion. Also, immune-related adverse events have often occurred due to the off-target binding of therapeutics to normal tissues after systematic treatment. In light of this, we have developed a synergistic immunotherapy strategy that locally targets the immunoinhibitory receptor programmed cell death protein 1 (PD1) and immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) for the treatment of melanoma through a microneedle-based transcutaneous delivery approach. The embedded immunotherapeutic nanocapsule loaded with anti-PD1 antibody (aPD1) is assembled from hyaluronic acid modified with 1-methyl-dl-tryptophan (1-MT), an inhibitor of IDO. This formulation method based on the combination strategy of "drug A in carriers formed by incorporation of drug B" facilitates the loading capacity of therapeutics. Moreover, the resulting delivery device elicits the sustained release and enhances retention of checkpoint inhibitors in the tumor microenvironment. Using a B16F10 mouse melanoma model, we demonstrate that this synergistic treatment has achieved potent antitumor efficacy, which is accompanied by enhanced effective T cell immunity as well as reduced immunosuppression in the local site.