title: CD28 costimulation Impairs the efficacy of a redirected t-cell antitumor attack in the presence of regulatory t cells which can be overcome by preventing Lck activation.
abstract: Adoptive T-cell transfer showed promising efficacy in recent trials raising interest in T cells with redirected specificity against tumors. T cells were engineered with a chimeric antigen receptor (CAR) with predefined binding and CD3ζ signaling to initiate T-cell activation. CD28 costimulation provided by a CD28-CD3ζ signaling CAR moreover improved T cell activation and persistence; however, it failed to meet the expectations with respect to mounting attacks against solid tumors infiltrated with regulatory T (Treg) cells. We revealed that a CD28 CAR-redirected T-cell attack is accompanied by higher numbers of Treg cells infiltrating the tumor and is less efficient against cancer cells in presence of Treg cells than a CD3ζ CAR T-cell attack. Deletion of the lck binding moiety in the CD28 CAR endodomain, however, improved redirected anti-tumor activity in presence of Treg cells without impairing interferon-γ (IFN-γ) secretion, proliferation, and cytolysis. CD28 modification abrogated interleukin-2 (IL-2) induction upon CAR engagement which in turn is no longer available to sustain Treg cell persistence. CARs with the modified CD28 endodomain thereby expedite the implementation of adoptive T-cell therapy in patients with a variety of cancer types that are heavily infiltrated by Treg cells.
authors.affiliation: Department I of Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: David M
authors.initials: DM
authors.lastname: Kofler
authors.forename: Markus
authors.initials: M
authors.lastname: Chmielewski
authors.forename: Gunter
authors.initials: G
authors.lastname: Rappl
authors.forename: Anja
authors.initials: A
authors.lastname: Hombach
authors.forename: Tobias
authors.initials: T
authors.lastname: Riet
authors.forename: Annette
authors.initials: A
authors.lastname: Schmidt
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Hombach
authors.forename: Clemens-Martin
authors.initials: CM
authors.lastname: Wendtner
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)