Hyaluronidase Enhances Targeting of Hydrogel-Encapsulated Anti-CTLA-4 to Tumor Draining Lymph Nodes and Improves Anti-Tumor Efficacy

Immunotherapy targeting checkpoint inhibitors, such as CTLA-4 and/or PD-1, has emerged as a leading cancer therapy. While their combination produces superior efficacy compared to monotherapy, it also magnifies inflammatory and autoimmune toxicity that limits clinical utility. We previously reported...

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Bibliographic Details
Published in:Gels 2022-05, Vol.8 (5), p.284
Main Authors: Harui, Airi, Roth, Michael D
Format: Article
Language:English
Subjects:
Animals
anti-CTLA-4
Antibodies
Anticancer properties
Brief Report
checkpoint inhibitor blockade
Encapsulation
Hyaluronic acid
hyaluronidase
hydrogel
Hydrogels
Hypotheses
Immunotherapy
Labeling
Lymphatic system
peri-tumor injection
Survival
Toxicity
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Summary:Immunotherapy targeting checkpoint inhibitors, such as CTLA-4 and/or PD-1, has emerged as a leading cancer therapy. While their combination produces superior efficacy compared to monotherapy, it also magnifies inflammatory and autoimmune toxicity that limits clinical utility. We previously reported that a peri-tumor injection of low-dose hydrogel-encapsulated anti-CTLA-4 produced anti-tumor responses that were equal to, or better than, systemic dosing despite a >80% reduction in total dose. Injection of hydrogel-encapsulated anti-CTLA-4 was associated with low serum exposure and limited autoimmune toxicity, but still synergized with anti-PD-1. In this report, we employ live and ex vivo imaging to examine whether peri-tumor administration specifically targets anti-CTLA-4 to tumor-draining lymph nodes (TDLN) and whether the incorporation of hyaluronidase enhances this effect. Tumor-free survival analysis was also used to measure the impact of hyaluronidase on tumor response. Compared to systemic dosing, peri-tumor injection of hydrogel-encapsulated anti-CTLA-4/DyLight 800 resulted in preferential labeling of TDLN. Incorporating hyaluronidase within the hydrogel improved the rapidity, intensity, and duration of TDLN labeling and significantly improved tumor-free survival. We conclude that hydrogel-encapsulated anti-CTLA acts as a localized antibody reservoir and that inclusion of hyaluronidase optimizes the blockade of CTLA-4 in TDLN and thereby imparts superior anti-tumor immunity.
ISSN:2310-2861
2310-2861
DOI:10.3390/gels8050284