title: Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity.
abstract: Two major challenges facing cancer immunotherapy are the relatively low therapeutic efficacy and the potential side effects. New drug delivery system and efficient drug combination are required to overcome these challenges. We utilize an alginate hydrogel system to locally deliver 2 FDA-approved drugs, celecoxib and programmed death 1 (PD-1) monoclonal antibody (mAb), to treat tumor-bearing mice. In two cancer models, B16-F10 melanoma and 4T1 metastatic breast cancer, the alginate hydrogel delivery system significantly improves the antitumor activities of celecoxib (CXB), PD-1 mAb, or both combined. These effects are associated with the sustained high concentrations of the drugs in peripheral circulation and within tumor regions. Strikingly, the simultaneous dual local delivery of celecoxib and PD-1 from this hydrogel system synergistically enhanced the presence of CD4+inteferon (IFN)-γ+and CD8+IFN-γ+T cells within the tumor as well as in the immune system. These effects are accompanied with reduced CD4+FoxP3+regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the tumor, reflecting a weakened immuosuppressive response. Furthermore, this combinatorial therapy increases the expression of two anti-angiogenic chemokines C-X-C motif ligand (CXCL) 9 and CXCL10, and suppresses the intratumoral production of interleukin (IL)-1, IL-6, and cycloxygenase-2 (COX2), suggesting a dampened pro-tumor angiogenic and inflammatory microenvironment. This alginate-hydrogel-mediated, combinatorial therapy of celecoxib and PD-1 mAb provides a potential valuable regimen for treating human cancer.
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
authors.forename: Min
authors.initials: M
authors.lastname: Fang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Song
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Ren
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan School of Medicine , Ann Arbor, MI, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Medical Research Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
keywords: 20 blockade; Alginate hydrogel; MDSC; PD-1; Treg; angiogenesis; antitumor immunity; cancer immunotherapy; celecoxib; effector T cells; inflammation