In Situ Crosslinked Hydrogel Depot for Sustained Antibody Release Improves Immune Checkpoint Blockade Cancer Immunotherapy.

Jihoon Kim,David M. Francis,Susan N. Thomas

doi:10.3390/nano11020471

Abstract

The therapeutic inhibition of immune checkpoints, including cytotoxic T lymphocyte-associated protein (CTLA)-4 and programmed cell death 1 (PD-1), through the use of function blocking antibodies can confer improved clinical outcomes by invigorating CD8+ T cell-mediated anticancer immunity. However, low rates of patient responses and the high rate of immune-related adverse events remain significant challenges to broadening the benefit of this therapeutic class, termed immune checkpoint blockade (ICB). To overcome these significant limitations, controlled delivery and release strategies offer unique advantages relevant to this therapeutic class, which is typically administered systemically (e.g., intravenously), but more recently, has been shown to be highly efficacious using locoregional routes of administration. As such, in this paper, we describe an in situ crosslinked hydrogel for the sustained release of antibodies blocking CTLA-4 and PD-1 signaling from a locoregional injection proximal to the tumor site. This formulation results in efficient and durable anticancer effects with a reduced systemic toxicity compared to the bolus delivery of free antibody using an equivalent injection route. This formulation and strategy thus represent an approach for achieving the efficient and safe delivery of antibodies for ICB cancer immunotherapy.

Highlights

Immune checkpoint blockade (ICB) therapy has transformed medical oncology within the last decade [1,2]
The most well-established are therapies inhibiting the functions of cytotoxic T lymphocyteassociated protein (CTLA)-4, which is expressed on T lymphocytes and outcompetes CD28 for engagement with CD80/CD86 on antigen presenting cells (APCs) to suppress cytotoxic CD8+ T cell priming [1,2,3]
Pluronic® F127 was selected as a polymeric backbone for the immune checkpoint blockade (ICB) antibody-releasing hydrogel depot due to its amphiphilic nature, which facilitates the sustained release of various hydrophobic and hydrophilic drugs [35]

Summary

Introduction

Immune checkpoint blockade (ICB) therapy has transformed medical oncology within the last decade [1,2]. Administration into the tissues i.l. to the tumor site, which only resulted in antibody accumulation within lymph nodes co-draining the tumor, was as effective as i.t. therapy This administration scheme conferred dose sparing benefits, suggesting the potential for ICB antibodies administered into peripheral tissues rather than systemically. We leveraged thermosensitive hydrogels formed from bare Pluronic® F127 to prolong the ICB antibody half-life at the site of injection ~20 fold (from ~2 to 20 h) [5] Further prolonging this in vivo residence time has the potential to further improve the therapeutic benefits, and patient compliance, by minimizing the need for repeated administrations. We demonstrate the therapeutic potential of the sustained release of ICB antibodies from in situ crosslinked hydrogels injected i.l. in terms of anticancer effects (Scheme 1). The benefits of ICB for T cell instruction are prolonged, improving the anti-tumor effects of ICB immunotherapy

Materials

Synthesis and Characterization of F127-pSH

Statistics

Results and Discussion