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

• Published in: Science translational medicine Vol. 9; no. 415
• Main Authors: Ishihara, Jun, Fukunaga, Kazuto, Ishihara, Ako, Larsson, Hans M, Potin, Lambert, Hosseinchi, Peyman, Galliverti, Gabriele, Swartz, Melody A, Hubbell, Jeffrey A
• Format: Journal Article
• Language: English
• Published: United States 08.11.2017
• Subjects: Animals; Antibodies - metabolism; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; CTLA-4 Antigen; Disease Models, Animal; Extracellular Matrix - metabolism; Extracellular Matrix Proteins - metabolism; Fibrinolysin - metabolism; Genetic Engineering; Heparin - metabolism; Immunity; Immunotherapy; Lymphocytes, Tumor-Infiltrating - immunology; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice, Inbred C57BL; Peptides - pharmacology; Peptides - therapeutic use; Placenta Growth Factor - chemistry; Treatment Outcome
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aan0401

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-2 ). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2 -anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2 -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-2 -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.