Adoptive cell therapy(ACT)is an immunotherapy strategy for cancer that has seen widespread clinical success.During ACT,patient-derived lymphocytes are stimulated with the antigen of interest ex vivo,proliferated,then ...Adoptive cell therapy(ACT)is an immunotherapy strategy for cancer that has seen widespread clinical success.During ACT,patient-derived lymphocytes are stimulated with the antigen of interest ex vivo,proliferated,then returned to the patient to initiate an antigen-specific antitumor response.While effective,this process is resource-intensive and logistically impossible for many patients.Particulate artificial antigen presenting cells(aAPCs)offer a potential“off-the-shelf”alternative to ex vivo ACT.While particulate aAPCs perform well in vitro,they have had limited success in vivo due to poor bioavailability after injection.Barriers to bioavailability include rapid clearance,unfavorable biodistribution,and inadequate interactions with CD8+T cells at sites of interest.Biomaterial properties such as elasticity have been shown to vastly impact the bioavailability and particle-cell interactions,but this has yet to be investigated in the context of aAPCs for in vivo T-cell stimulation.Previous literature likewise indicates that biomaterial properties,especially elasticity,can modulate T-cell activation in vitro.With the goal of creating a more biomimetic,next-generation particulate aAPC,we developed a poly(ethylene)glycol hydrogel particle platform with tunable elasticity to investigate the impact of elasticity on antigen-specific T cell activation for in vivo adoptive transfer.Using this knowledge,we were able to gain more precise control over in vivo T cell activation and investigate possible mechanisms including the effects of aAPC elasticity on T cell binding,macrophage uptake,and the protein corona.展开更多
Artificial antigen-presenting cells are expected to stimulate the expansion and acquisition of optimal therapeutic features of T cells before infusion. Here CD32 that binds to a crystallizable fragment of IgG monoclon...Artificial antigen-presenting cells are expected to stimulate the expansion and acquisition of optimal therapeutic features of T cells before infusion. Here CD32 that binds to a crystallizable fragment of IgG monoclonal antibody was genetically expressed on human K562 leukemia cells to provide a ligand for T-cell receptor. CD86 and 4-1BBL, which are ligands of co-stimulating receptors of CD28 and 4-1BB, respectively, were also expressed on K562 cells. Then we accomplished the artificial antigen-presenting cells by coupling K32/CD86/4-1BBL cell with OKT3 monoclonal antibody against CD3, named K32/CD86/4-1BBL/OKT3 cells. These artificial modified cells had the abilities of inducing CD8^＋ T cell activation, promoting CD8^＋ T cell proliferation, division, and long-term growth, inhibiting CD8^＋ T cell apoptosis, and enhancing CD8^＋ T cell secretion of IFN-T and perforin. Furthermore, antigen-specific cytotoxic T lymphocytes could be retained in the culture stimulated with K32/CD86/4-1BBL/OKT3 cells at least within 28 days. This approach was robust, simple, reproducible and economical for expansion and activation of CD8^＋ T cells and may have important therapeutic implications for adoptive immunotherapy. Cellular ＆ Molecular Immunology.展开更多
基金the NIH for support of this research(P41EB028239)the National Science Foundation Graduate Research Fellowship(Nos.DGE-1746891(SEW)and DGE-1746891(SRS)).
文摘Adoptive cell therapy(ACT)is an immunotherapy strategy for cancer that has seen widespread clinical success.During ACT,patient-derived lymphocytes are stimulated with the antigen of interest ex vivo,proliferated,then returned to the patient to initiate an antigen-specific antitumor response.While effective,this process is resource-intensive and logistically impossible for many patients.Particulate artificial antigen presenting cells(aAPCs)offer a potential“off-the-shelf”alternative to ex vivo ACT.While particulate aAPCs perform well in vitro,they have had limited success in vivo due to poor bioavailability after injection.Barriers to bioavailability include rapid clearance,unfavorable biodistribution,and inadequate interactions with CD8+T cells at sites of interest.Biomaterial properties such as elasticity have been shown to vastly impact the bioavailability and particle-cell interactions,but this has yet to be investigated in the context of aAPCs for in vivo T-cell stimulation.Previous literature likewise indicates that biomaterial properties,especially elasticity,can modulate T-cell activation in vitro.With the goal of creating a more biomimetic,next-generation particulate aAPC,we developed a poly(ethylene)glycol hydrogel particle platform with tunable elasticity to investigate the impact of elasticity on antigen-specific T cell activation for in vivo adoptive transfer.Using this knowledge,we were able to gain more precise control over in vivo T cell activation and investigate possible mechanisms including the effects of aAPC elasticity on T cell binding,macrophage uptake,and the protein corona.
基金the National Natural Science Foundation of China（No.30400399,No.30671917）the Natural Science Fund of Jiangsu Province（BK2004404） the Natural Science Fund of the Educational Committee of Jiangsu Province（04KJB320162） in China.
文摘Artificial antigen-presenting cells are expected to stimulate the expansion and acquisition of optimal therapeutic features of T cells before infusion. Here CD32 that binds to a crystallizable fragment of IgG monoclonal antibody was genetically expressed on human K562 leukemia cells to provide a ligand for T-cell receptor. CD86 and 4-1BBL, which are ligands of co-stimulating receptors of CD28 and 4-1BB, respectively, were also expressed on K562 cells. Then we accomplished the artificial antigen-presenting cells by coupling K32/CD86/4-1BBL cell with OKT3 monoclonal antibody against CD3, named K32/CD86/4-1BBL/OKT3 cells. These artificial modified cells had the abilities of inducing CD8^＋ T cell activation, promoting CD8^＋ T cell proliferation, division, and long-term growth, inhibiting CD8^＋ T cell apoptosis, and enhancing CD8^＋ T cell secretion of IFN-T and perforin. Furthermore, antigen-specific cytotoxic T lymphocytes could be retained in the culture stimulated with K32/CD86/4-1BBL/OKT3 cells at least within 28 days. This approach was robust, simple, reproducible and economical for expansion and activation of CD8^＋ T cells and may have important therapeutic implications for adoptive immunotherapy. Cellular ＆ Molecular Immunology.
