CAR T-Cell Therapies in Hematologic Tumors
Chimeric antigen receptors (CARs) are genetically constructed hybrid receptors that consist of a single-chain variable fragment (scFv) of a monoclonal antibody as the antigen-binding extracellular domain, an intracellular CD3ζ chain as the T cell receptor (TCR) signaling domain, and an additional co-signaling domain, mainly CD28 or 4-1BB, to deliver co-stimulation. Cytotoxic activity of CAR T cells is determined by antigen-binding to the scFv leading to the phosphorylation of CD3ζ and to additional signaling cascades by co-stimulating domains. This mechanism recapitulates intracellular signaling following T cell activation through the TCR complex, although in an MHC-independent fashion.
Since their discovery in the late 1980s, CAR T cells have shown very promising clinical results, and several trials are currently being conducted worldwide to establish their role in cancer treatment. Most successful clinical results have been observed with CD19-directed CAR T cells in B-cell lymphoproliferative disorders, which led to the recent approval of two CAR-T cell therapies by F.D.A. and E.M.A. for the treatment of non-Hodgkin lymphomas and acute lymphoblastic leukemias [Kymriah (Novartis) and Yescarta (Kite/Gilead)]. However, in other hematological malignancies (e.g. T-cell lymphomas, multiple myeloma, and myeloid leukemias) and in solid cancers, many challenges still need to be overcome for successful therapies, namely as the scarcity of effective tumor antigens identified to date and the presence of more repressive tumor microenvironments hampering CAR T-cell functions.
This Research Topic aims to provide a comprehensive overview of the current roles of CAR T-cell therapies in several hematological malignancies and solid tumors and to highlight challenges for future developments in the armamentarium of cancer treatment.
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Immunotherapy: Open access