The wide prevalence of BRAF mutations in diagnosed
melanomas drove the clinical advancement of BRAF inhibitors in combination with
immune checkpoint blockade for treatment of advanced disease. However, deficits in therapeutic potencies and safety profiles motivate the development of more effective strategies that improve the combination
therapy's therapeutic index. Herein, we demonstrate the benefits of a locoregional chemoimmunotherapy delivery system, a novel thermosensitive
hydrogel comprised of
gelatin and Pluronic®
F127 components already widely used in humans in both commercial and clinical products, for the co-delivery of a small molecule BRAF inhibitor with
immune checkpoint blockade antibody for the treatment of BRAF-mutated
melanoma. In vivo evaluation of administration route and immune checkpoint target effects revealed intratumoral administration of antagonistic
programmed cell death protein 1 antibody (aPD-1) lead to potent antitumor
therapy in combination with BRAF inhibitor
vemurafenib. The thermosensitive F127-g-Gelatin
hydrogel that was evaluated in multiple murine models of BRAF-mutated
melanoma that facilitated prolonged local drug release within the
tumor (>1 week) substantially improved local
immunomodulation,
tumor control, rates of
tumor response, and animal survival. Thermosensitive F127-g-Gelatin
hydrogels thus improve upon the clinical benefits of
vemurafenib and aPD-1 in a locoregional chemoimmunotherapy approach for the treatment of BRAF-mutated
melanoma.