title: GD2-specific CAR T Cells Undergo Potent Activation and Deletion Following Antigen Encounter but can be Protected From Activation-induced Cell Death by PD-1 Blockade.
abstract: Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological "space", functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1(+) tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients.
authors.affiliation: Translational Oncology Laboratory Centre for Cancer Biology, SA Pathology, and University of South Australia, Adelaide, South Australia. Electronic address: Tessa.Gargett@health.sa.gov.au.
authors.forename: Tessa
authors.initials: T
authors.lastname: Gargett
authors.affiliation: Translational Oncology Laboratory Centre for Cancer Biology, SA Pathology, and University of South Australia, Adelaide, South Australia.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yu
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Feigin Center, Houston, Texas, USA; Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Feigin Center, Houston, Texas, USA; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Yvon
authors.affiliation: Experimental Therapeutics Laboratory, Sansom Institute and Hanson Institute, School of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia.
authors.forename: Susan N
authors.initials: SN
authors.lastname: Christo
authors.affiliation: Experimental Therapeutics Laboratory, Sansom Institute and Hanson Institute, School of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia; Robinson Research Institute, Discipline of Obstetrics and Gynecology, School of Medicine, University of Adelaide, Adelaide, South Australia; Discipline of Medicine, University of Adelaide, Adelaide, South Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Hayball
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, South Australia.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Feigin Center, Houston, Texas, USA.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.affiliation: Translational Oncology Laboratory Centre for Cancer Biology, SA Pathology, and University of South Australia, Adelaide, South Australia; Discipline of Medicine, University of Adelaide, Adelaide, South Australia; Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005732:Gangliosides / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D009362:Neoplasm Metastasis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D005732:Gangliosides; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; C582435:pembrolizumab