Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CART cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3ζ-and CD28-containing endodomain signaling chain. We tested STOP-CART cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CART cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CART cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies. T cells engineered with CARs, hybrid molecules linking antigen binding to T-cell signaling endodomains, have mediated potent and durable responses against both chronic and acute B cell leukemias 1-4. CART cell therapy, however, is frequently associated with lifethreatening side effects, including cytokine release syndrome (CRS) and neurotoxicity. The clinical development of CART cells against solid tumors has proven challenging, but there is great optimism that next-generation CART cells will bring benefit to a broader range of cancer patients 5. Indeed, it is now well understood that physical and immunometabolic barriers upregulated in the solid tumor microenvironment as well as prolonged exposure to antigens can impair T-cell function and drive T-cell exhaustion 6. Innovative engineering strategies, such as the expression of cytokines, chemokines, decoy molecules or stimulatory ligands, are being developed to overcome these obstacles and have shown favorable preclinical responses 6-8. Safety, however, remains an important barrier to clinical entry because most solid tumor antigens targeted to date are also found in healthy tissues, sometimes leading to serious on-target off-tumor toxicity 9. The ability to control CART cell activity on command could greatly accelerate the clinical development of cellular immunotherapies. The above considerations have driven the development of CART cell control and safety systems 5 , such as drug-inducible suicide switches 10,11 , coinhibitory receptor (i)CARs that upon engagement with specific antigens suppress effector function 12 and split-signaling CART cells that require co-engagement of two ligands for full T-cell activation 13. SUPRA (split, universal and programmable) CARs 14 and a variety of universal CARs 15,16 have been developed that require administration of an adaptor protein to link nontumor antigen binding CART cells to tumor cells. While these approaches offer the possibility to sequentially target different tumor antigens (for ...
Emerging insights into cellular senescence highlight the relevance of senescence in musculoskeletal disorders, which represent the leading global cause of disability. Cellular senescence was initially described by Hayflick et al. in 1961 as an irreversible nondividing state in in vitro cell culture studies. We now know that cellular senescence can occur in vivo in response to various stressors as a heterogeneous and tissue-specific cell state with a secretome phenotype acquired after the initial growth arrest. In the past two decades, compelling evidence from preclinical models and human data show an accumulation of senescent cells in many components of the musculoskeletal system. Cellular senescence is therefore a defining feature of age-related musculoskeletal disorders, and targeted elimination of these cells has emerged recently as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration of the skeleton and skeletal muscles. In this review, we summarize evidence of the role of senescent cells in the maintenance of bone homeostasis during childhood and their contribution to the pathogenesis of chronic musculoskeletal disorders, including osteoporosis, osteoarthritis, and sarcopenia. We highlight the diversity of the senescent cells in the microenvironment of bone, joint, and skeletal muscle tissue, as well as the mechanisms by which these senescent cells are involved in musculoskeletal diseases. In addition, we discuss how identifying and targeting senescent cells might positively affect pathologic progression and musculoskeletal system regeneration.
Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback Graphical abstract Highlights d A complete kinetic model of acute infection by the coxsackievirus B3 enterovirus d Enteroviral replication organelles accelerate biochemistry on membrane surfaces d Type I interferon exaggerates different enteroviral susceptibilities of host cells d A common polymorphism in MAVS alters host-cell susceptibility to coxsackievirus B3
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