title: Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma.
abstract: Adoptive T-cell therapy recently achieved impressive efficacy in early phase trials, in particular in hematologic malignancies, strongly supporting the notion that the immune system can control cancer. A current strategy of favor is based on ex vivo-engineered patient T cells, which are redirected by a chimeric antigen receptor (CAR) and recognize a predefined target by an antibody-derived binding domain. Such CAR T cells can substantially reduce the tumor burden as long as the targeted antigen is present on the cancer cells. However, given the tremendous phenotypic diversity in solid tumor lesions, a reasonable number of cancer cells are not recognized by a given CAR, considerably reducing the therapeutic success. This article reviews a recently described strategy for overcoming this shortcoming of the CAR T-cell therapy by modulating the tumor stroma by a CAR T-cell-secreted transgenic cytokine like interleukin-12 (IL-12). The basic process is that CAR T cells, when activated by their CAR, deposit IL-12 in the targeted tumor lesion, which in turn attracts an innate immune cell response toward those cancer cells that are invisible to CAR T cells. Such TRUCKs, T cells redirected for universal cytokine-mediated killing, exhibited remarkable efficacy against solid tumors with diverse cancer cell phenotypes, suggesting their evaluation in clinical trials.
authors: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Clinic I for Internal Medicine, University Hospital Cologne, Cologne, Germany.
authors: Markus
authors: M
authors: Chmielewski
authors: Andreas A
authors: AA
authors: Hombach
authors: Hinrich
authors: H
authors: Abken
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007113:Immunity, Innate; D007155:Immunologic Factors / Q000235:genetics / Q000378:metabolism; D056747:Immunomodulation; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D017154:Stromal Cells / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12
keywords: IL-12; T cell; adoptive cell therapy; chimeric antigen receptor; inducible cytokine; innate immunity; stroma