Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial.

Autor: Bagley SJ; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. sbagley@pennmedicine.upenn.edu., Binder ZA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Lamrani L; Clinical Immunology Laboratory, Institut Curie, Paris, France.; INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Marinari E; Agora Cancer Research Center, Lausanne, Switzerland.; Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland.; Swiss Cancer Center Léman, Lausanne and Geneva, Geneva, Switzerland.; Department of Oncology, University Hospital of Geneva, Geneva, Switzerland., Desai AS; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Nasrallah MP; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Maloney E; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Brem S; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Lustig RA; Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Kurtz G; Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Alonso-Basanta M; Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Bonté PE; INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France., Goudot C; INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France., Richer W; INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France.; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France., Piaggio E; INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France., Kothari S; Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA., Guyonnet L; Cytometry Platform, CurieCoreTech, Institut Curie, Paris, France., Guerin CL; Cytometry Platform, CurieCoreTech, Institut Curie, Paris, France., Waterfall JJ; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France.; INSERM U830, PSL University, Institut Curie Research Cente, Paris, France., Mohan S; Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Hwang WT; Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Tang OY; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Warren Alpert Medical School of Brown University, Providence, RI, USA., Logun M; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Bhattacharyya M; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Cooper Medical School of Rowan University, Camden, NJ, USA., Markowitz K; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Delman D; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Marshall A; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Wherry EJ; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Institute for Immunology and Immune Health, Cambridge, MA, USA., Amigorena S; INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France., Beatty GL; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Brogdon JL; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Hexner E; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Migliorini D; Agora Cancer Research Center, Lausanne, Switzerland.; Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland.; Swiss Cancer Center Léman, Lausanne and Geneva, Geneva, Switzerland.; Department of Oncology, University Hospital of Geneva, Geneva, Switzerland., Alanio C; Clinical Immunology Laboratory, Institut Curie, Paris, France. cecile.alanio@curie.fr.; INSERM U932, PSL University, Immunity and Cancer, Institut Curie Research Center, Paris, France. cecile.alanio@curie.fr.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. cecile.alanio@curie.fr., O'Rourke DM; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2024 Mar; Vol. 5 (3), pp. 517-531. Date of Electronic Publication: 2024 Jan 12.
DOI: 10.1038/s43018-023-00709-6
Abstrakt: We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII + glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9-6.0 months) and median overall survival (11.8 months; 90% CI, 9.2-14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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