Molecular Approaches to Safe and Controlled Engineered T-cell Therapy

Abstract

Chimeric antigen receptor-modified T-cell therapy (CAR-T therapy) is one of the fastest developing areas of immuno-oncology. Over the past decade, it has revolutionized the cell therapy modality and expedited its pace of development, from optimization of the structure of chimeric antigen receptors and animal model experiments to successful clinical application. The initial designs of the CAR configuration focused on increasing T-cell activation, cytotoxicity, and persistence. However, the first attempts to treat patients with CAR T cells have demonstrated the need for increased safety and controlled activation of genetically modified T cells. Herein, we summarize the different molecular approaches to engineering chimeric antigen receptors for reducing the potential clinical risks of T-cell therapy. KEYWORDS chimeric antigen receptors, T-cells, cell therapy, cancer cells.

Bcl-2 Enhances Chimeric Antigen Receptor T Cell Persistence by Reducing Activation-Induced Apoptosis

“…Bcl-2 is overexpressed in various types of cancer and is a key mediator for chemotherapy resistance [ 37 ]. An inducible death-switch, such as Herpes simplex virus thymidine kinase (HSV-TK) [ 44 ], inducible caspase-9 [ 45 ], or Rituximab binding epitope [ 46 ], will provide an alternative strategy for eliminating these cells if required.…”

Barnase-barstar Specific Interaction Regulates Car-T Cells Cytotoxic Activity toward Malignancy

“…of the clinical side effects [3][4][5][6]. A numerous attempts to regulate tumor cytotoxicity caused by CAR-T cells were accomplished recently [7][8][9].…”

Neutrophil Extracellular Traps (NETs): Opportunities for Targeted Therapy

“…CAR-T therapy of hematological cancer, taking into account the approaches of personalized medicine, is increasingly becoming a reality [ 50 , 51 ]. At the same time, the possibilities of CAR-T therapy for solid tumors remain very limited [ 52 ]. It is likely that NETs, in this case, will become important in efforts to overcome the barriers to effective CAR-T therapy.…”