title: Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo.
abstract: Persistence of T cells engineered with chimeric antigen receptors (CARs) has been a major barrier to use of these cells for molecularly targeted adoptive immunotherapy. To address this issue, we created a series of CARs that contain the T cell receptor-zeta (TCR-zeta) signal transduction domain with the CD28 and/or CD137 (4-1BB) intracellular domains in tandem. After short-term expansion, primary human T cells were subjected to lentiviral gene transfer, resulting in large numbers of cells with >85% CAR expression. In an immunodeficient mouse xenograft model of primary human pre-B-cell acute lymphoblastic leukemia, human T cells expressing anti-CD19 CARs containing CD137 exhibited the greatest antileukemic efficacy and prolonged (>6 months) survival in vivo, and were significantly more effective than cells expressing CARs containing TCR-zeta alone or CD28-zeta signaling receptors. We uncovered a previously unrecognized, antigen-independent effect of CARs expressing the CD137 cytoplasmic domain that likely contributes to the enhanced antileukemic efficacy and survival in tumor bearing mice. Furthermore, our studies revealed significant discrepancies between in vitro and in vivo surrogate measures of CAR efficacy. Together these results suggest that incorporation of the CD137 signaling domain in CARs should improve the persistence of CARs in the hematologic malignancies and hence maximize their antitumor activity.
authors.affiliation: Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-5160, USA. milone@mail.med.upenn.edu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Milone
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Fish
authors.forename: Carmine
authors.initials: C
authors.lastname: Carpenito
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.forename: Gwendolyn K
authors.initials: GK
authors.lastname: Binder
authors.forename: David
authors.initials: D
authors.lastname: Teachey
authors.forename: Minu
authors.initials: M
authors.lastname: Samanta
authors.forename: Mehdi
authors.initials: M
authors.lastname: Lakhal
authors.forename: Brian
authors.initials: B
authors.lastname: Gloss
authors.forename: Gwenn
authors.initials: G
authors.lastname: Danet-Desnoyers
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D016086:Lentivirus / Q000235:genetics; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9