title: Arming cytokine-induced killer cells with chimeric antigen receptors: CD28 outperforms combined CD28-OX40 "super-stimulation".
abstract: Cytokine-induced killer (CIK) cells raised interest for use in cellular antitumor therapy due to their capability to recognize and destroy autologous tumor cells in a HLA-independent fashion. The antitumor attack of CIK cells, predominantly consisting of terminally differentiated CD8(+)CD56(+) cells, can be improved by redirecting by a chimeric antigen receptor (CAR) that recognizes the tumor cell and triggers CIK cell activation. The requirements for CIK cell activation were, however, so far less explored and are likely to be different from those of "younger" T cells. We revealed that CD28 and OX40 CARs produced higher interferon- secretion as compared with the first-generation ζ-CAR; CD28-ζ and the third-generation CD28-ζ-OX40 CAR, however, performed similar in modulating most CIK cell effector functions. Compared with the CD28-ζ CAR, however, the CD28-ζ-OX40 CAR accelerated terminal maturation of CD56(+) CIK cells producing high frequencies in activation-induced cell death (AICD) and reduced antitumor efficiency in vivo. Consequently, CD28-ζ CAR CIK cells of CD56(-) phenotype were superior in redirected tumor cell elimination. CAR-mediated CIK cell activation also increased antigen-independent target cell lysis; the CD28-ζ CAR was more efficient than the CD28-ζ-OX40 CAR. Translated into therapeutic strategies, CAR-redirected CIK cells benefit from CD28 costimulation; "super-costimulation" by the CD28-ζ-OX40 CAR, however, performed less in antitumor efficacy due to increased AICD.
authors.affiliation: 1] Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany [2] Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Hombach
authors.forename: Gunter
authors.initials: G
authors.lastname: Rappl
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D055612:Cytokine-Induced Killer Cells / Q000276:immunology* / Q000637:transplantation*; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D053262:Receptors, OX40 / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D019002:CD56 Antigen; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; D011993:Recombinant Fusion Proteins