title: Chitosan thermogels for local expansion and delivery of tumor-specific T lymphocytes towards enhanced cancer immunotherapies.
abstract: The success of promising anti-cancer adoptive cell therapies relies on the abilities of the perfused CD8(+) T lymphocytes to gain access to and persist within the tumor microenvironment to carry out their cytotoxic functions. We propose a new method for their local delivery as a living concentrate, which may not only reduce the numbers of cells required for treatment but also enhance their site-specific mobilization. Using combinations of sodium hydrogen carbonate and phosphate buffer as gelling agents, novel injectable chitosan-based biocompatible thermogels (CTGels) having excellent mechanical properties and cytocompatibility have been developed. Three thermogel formulations with acceptable physicochemical properties, such as physiological pH and osmolality, macroporosity, and gelation rates were compared. The CTGel2 formulation outperformed the others by providing an environment suitable for the encapsulation of viable CD8(+) T lymphocytes, supporting their proliferation and gradual release. In addition, the encapsulated T cell phenotypes were influenced by surrounding conditions and by tumor cells, while maintaining their capacity to kill tumor cells. This strongly suggests that cells encapsulated in this formulation retain their anti-cancer functions, and that this locally injectable hydrogel may be further developed to complement a wide variety of existing immunotherapies.
authors.affiliation: Laboratoire d'Immuno-Oncologie, ICM, Université de Montréal/CHUM Research Center (CRCHUM), Montréal, QC, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Monette
authors.affiliation: Department of Mechanical Engineering, École de technologie supérieure (ETS)/ Laboratory of Endovascular Biomaterials (LBeV), CRCHUM, Montréal, QC, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ceccaldi
authors.affiliation: Department of Mechanical Engineering, École de technologie supérieure (ETS)/ Laboratory of Endovascular Biomaterials (LBeV), CRCHUM, Montréal, QC, Canada.
authors.forename: Elias
authors.initials: E
authors.lastname: Assaad
authors.affiliation: Department of Mechanical Engineering, École de technologie supérieure (ETS)/ Laboratory of Endovascular Biomaterials (LBeV), CRCHUM, Montréal, QC, Canada. Electronic address: sophie.lerouge@etsmtl.ca.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lerouge
authors.affiliation: Laboratoire d'Immuno-Oncologie, ICM, Université de Montréal/CHUM Research Center (CRCHUM), Montréal, QC, Canada. Electronic address: rejean.lapointe@umontreal.ca.
authors.forename: Réjean
authors.initials: R
authors.lastname: Lapointe
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D048271:Chitosan / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005782:Gels / Q000494:pharmacology*; D006801:Humans; D007167:Immunotherapy; D007267:Injections; D007680:Kidney Neoplasms / Q000276:immunology* / Q000628:therapy*; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008422:Materials Testing; D010641:Phenotype; D016062:Porosity; D051381:Rats; D012212:Rheology; D013696:Temperature
chemical_list: D005782:Gels; D048271:Chitosan
keywords: Cancer; Chitosan; Hydrogel; Immunotherapy; Injectable; T lymphocytes