Genetic modification of T cells for cancer therapy.
The use of immune cells with restricted specificities for the treatment of cancer is a rapidly emerging area of clinical research. Chimeric receptors composed of the single-chain variable domain of murine antibodies and human signaling molecules are a promising tool to redirect the specificity of autologous or allogeneic immune cells. The success of this approach depends on the identification of target molecules expressed preferentially on cancer cells. Moreover, appropriate primary and secondary stimuli must be delivered to generate vigorous and durable immune responses. Since cancer cells often lack ligands for key co-stimulatory molecules, the addition of molecules such as CD28 or 4-1BB to the chimeric receptors can significantly improve their function. Studies in vitro and in animal models indicate that immune cells expressing chimeric receptors can have remarkable anti-cancer activity, while experimental and clinical data indicate that long-term persistence of adoptively transferred cells is feasible. Therefore, testing of this approach in clinical trials is warranted. We here review the principles and methodologies for designing chimeric receptors and delivering them into immune cells, as well as some of the potential complications associated with this form of cell therapy.
Departments of Hematology-Oncology, University of Tennessee College of Medicine, Memphis, TN, USA.
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D015703:Antigens, CD; D018941:Antigens, CD19 / Q000096:biosynthesis; D018106:CD28 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008024:Ligands; D008954:Models, Biological; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D015703:Antigens, CD; D018941:Antigens, CD19; D018106:CD28 Antigens; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9