title: A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors.
abstract: Chimeric antigen receptor (CAR)-modified adoptive T-cell therapy has been successfully applied to the treatment of hematologic malignancies, but faces many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced in both naturally occurring and genetically modified tumor-infiltrating lymphocytes (TIL) by inhibitory receptors (IR), namely PD1. We hypothesized that interfering with PD1 signaling would augment CAR T-cell activity against solid tumors. To address this possibility, we introduced a genetically engineered switch receptor construct, comprising the truncated extracellular domain of PD1 and the transmembrane and cytoplasmic signaling domains of CD28, into CAR T cells. We tested the effect of this supplement, "PD1CD28," on human CAR T cells targeting aggressive models of human solid tumors expressing relevant tumor antigens. Treatment of mice bearing large, established solid tumors with PD1CD28 CAR T cells led to significant regression in tumor volume due to enhanced CAR TIL infiltrate, decreased susceptibility to tumor-induced hypofunction, and attenuation of IR expression compared with treatments with CAR T cells alone or PD1 antibodies. Taken together, our findings suggest that the application of PD1CD28 to boost CAR T-cell activity is efficacious against solid tumors via a variety of mechanisms, prompting clinical investigation of this potentially promising treatment modality.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Raghuveer
authors.initials: R
authors.lastname: Ranganathan
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Chongyun
authors.initials: C
authors.lastname: Fang
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kheng
authors.initials: K
authors.lastname: Newick
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Albert
authors.initials: A
authors.lastname: Lo
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. edmund.moon@uphs.upenn.edu yangbing@exchange.upenn.edu.
authors.forename: Yangbing
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania. edmund.moon@uphs.upenn.edu yangbing@exchange.upenn.edu.
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Moon
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D020014:K562 Cells; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D047368:Tumor Burden / Q000276:immunology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell