We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy.
- Authors
Wang, Chao; Wang, Jinqiang; Zhang, Xudong; Yu, Shuangjiang; Wen, Di; Hu, Quanyin; Ye, Yanqi; Bomba, Hunter; Hu, Xiuli; Liu, Zhuang; Dotti, Gianpietro; Gu, Zhen
- Abstract
A ROS-responsive hydrogel scaffold controls release of gemcitabine and immune checkpoint inhibitor for enhanced antitumor activity. An antitumor two-step: Although cancer immunotherapy can be quite effective, it has a variety of drawbacks. Most patients still do not achieve remission, whereas those who respond to therapy often experience immune-related side effects. Wang et al. address both of these concerns by maximizing drug access to tumors and minimizing systemic exposure. To achieve this, the authors designed a hydrogel that they inject at the site of a tumor, where it forms a scaffold for sequential release of drugs. A cytotoxic chemotherapy is released first, killing some cancer cells before the release of most of an immune checkpoint inhibitor, which then stimulates antitumor immunity. With this approach, the authors demonstrate efficacy in mouse models of primary tumors, as well as those that recur after surgery. Patients with low-immunogenic tumors respond poorly to immune checkpoint blockade (ICB) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. Conversely, patients responding to ICB can experience various side effects. We have thus engineered a therapeutic scaffold that, when formed in situ, allows the local release of gemcitabine (GEM) and an anti–PD-L1 blocking antibody (aPDL1) with distinct release kinetics. The scaffold consists of reactive oxygen species (ROS)–degradable hydrogel that releases therapeutics in a programmed manner within the tumor microenvironment (TME), which contains abundant ROS. We found that the aPDL1-GEM scaffold elicits an immunogenic tumor phenotype and promotes an immune-mediated tumor regression in the tumor-bearing mice, with prevention of tumor recurrence after primary resection.
- Subjects
REACTIVE oxygen species; HYDROGELS; TUMOR microenvironment; LIGANDS (Biochemistry); SPONTANEOUS cancer regression
- Publication
Science Translational Medicine, 2018, Vol 10, Issue 429, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aan3682