Research ArticleCancer

Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events

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Science Translational Medicine  08 Nov 2017:
Vol. 9, Issue 415, eaan0401
DOI: 10.1126/scitranslmed.aan0401

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Keeping immunotherapy closer to home

Immune checkpoint inhibitors are gaining increasing prominence in the field of cancer because of their remarkable success record in many difficult-to-treat tumor types. Unfortunately, activation of the immune system against tumors does not occur in isolation, and these drugs are also associated with a host of immune side effects, which limit their usefulness. To decrease systemic toxicity, Ishihara et al. conjugated immune checkpoint antibodies to a matrix-binding peptide and showed that peritumoral injection of these conjugated antibodies results in their retention in tumor tissue, effective antitumor response, and systemic antitumor immunity with fewer adverse effects.

Abstract

Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)–super-affinity peptide derived from placenta growth factor–2 (PlGF-2123–144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123–144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123–144–anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123–144–anti–PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123–144–Abs increased tumor-infiltrating activated CD8+ and CD4+ T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.

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