title: The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma.
abstract: Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner.
  
  
  
  MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models.
  
  
  
  MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019- as compared with ibrutinib-treated mice (median survival not reached vs. 95 days, P < 0.005) but most mice receiving CTL019 monotherapy eventually relapsed. Therefore, we added ibrutinib to CTL019 and showed that 80% to 100% of mice in the CTL019 + ibrutinib arm and 0% to 20% of mice in the CTL019 arm, respectively, remained in long-term remission (P < 0.05).
  
  
  
  Combining CTL019 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients with MCL and other types of B-cell lymphoma. Clin Cancer Res; 22(11); 2684-96. ©2016 AACR.
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Marco
authors.initials: M
authors.lastname: Ruella
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Saad S
authors.initials: SS
authors.lastname: Kenderian
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Olga
authors.initials: O
authors.lastname: Shestova
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fraietta
authors.affiliation: Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Sohail
authors.initials: S
authors.lastname: Qayyum
authors.affiliation: Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Marcela V
authors.initials: MV
authors.lastname: Maus
authors.affiliation: Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Selene
authors.initials: S
authors.lastname: Nunez-Cruz
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Klichinsky
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Omkar U
authors.initials: OU
authors.lastname: Kawalekar
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Milone
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Simon F
authors.initials: SF
authors.lastname: Lacey
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mato
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Schuster
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. saar.gill@uphs.upenn.edu.
authors.forename: Saar
authors.initials: S
authors.lastname: Gill
authors.affiliation: Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016219:Immunotherapy, Adoptive; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000598123:CTL019 chimeric antigen receptor; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine