Local and Targeted Delivery of Immune Checkpoint Blockade Therapeutics

CONSPECTUS: Immune checkpoint blockade (ICB) therapy elicits antitumor response by inhibiting immune suppressor components, including programmed cell death protein 1 and its ligand (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Despite improved therapeutic efficacy, the clinical response rate is still unsatisfactory as revealed by the fact that only a minority of patients experience durable benefits. Additionally, "off-target" effects after systemic administration remain challenging for ICB treatment. To this end, the local and targeted delivery of ICB agents instead could be a potential solution to maximize the therapeutic outcomes while minimizing the side effects. In this Account, our recent studies directed at the development of different strategies for the local and targeted delivery of ICB agents are discussed. For example, transdermal microneedle patches loaded with anti-programmed death-1 antibody (aPD1) and anti-CTLA4 were developed to facilitate sustained release of ICB agents at the diseased sites. Triggered release could also be achieved by various stimuli within the tumor microenvironment, including low pH and abnormally expressed enzymes. Recently, the combination of an anti-programmed death-ligand 1 antibody (aPD-L1) loaded hollow-structured microneedle patch with cold atmospheric plasma (CAP) therapy was also reported. Microneedles provided microchannels to facilitate the transdermal transport of CAP and further induce immunogenic tumor cell death, which could be synergized by the local release of aPD-L1. In addition, in situ formed injectable or sprayable hydrogels were tailored to deliver immunomodulatory antibodies to the surgical bed to inhibit tumor recurrence after primary tumor resection. In paralell, inspired by the unique targeting ability of platelets toward the inflammatory sites, we engineered natural platelets decorated with aPD-L1 for targeted delivery after tumor resection to inhibit tumor recurrence. We further constructed a cell-cell combination delivery platform based on conjugates of platelets and hematopoietic stem cells (HSCs) for leukemia treatment. With the homing ability of HSCs to the bone marrow, the HSC-platelet-aPD1 assembly could effectively deliver aPD1 in an acute myeloid leukemia mouse model. Besides living cells, we also leveraged HEK293T-derived vesicles with PD1 receptors on their surfaces to disrupt the PD-1/PD-L1 immune inhibitory pathway. Moreover, the inner space of the vesicles allowed the packaging of an indoleamine 2,3-dioxygenase inhibitor, further reinforcing the therapeutic efficacy. A similar approach has also been demonstrated by genetically engineering platelets overexpressing PD1 receptor for postsurgical treatment. We hope the local and targeted ICB agent delivery methods introduced in this collection would further inspire the development of advanced drug delivery strategies to improve the efficiency of cancer treatment while alleviating side effects.