title: A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer.
abstract: OBJECTIVE
  In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease.
  
  
  BACKGROUND
  Genetically reprogrammed, patient-derived chimeric antigen receptor (CAR)-T lymphocytes with the ability to recognize predefined surface antigens with high specificity in a non-MHC restricted manner have shown increasing anti-tumor efficacy in preclinical and clinical studies. Folate receptor-α (FRα) is an ovarian cancer-specific tumor target; however, it is expressed at low levels in certain organs with risk for toxicity.
  
  
  METHODS
  Here we propose a phase I study testing the feasibility, safety and preliminary activity of FRα-redirected CAR-T cells bearing the CD137 (4-1BB) costimulatory domain, administered after lymphodepletion for the treatment of recurrent ovarian cancer. A novel trial design is proposed that maximizes safety features.
  
  
  METHODS
  This design involves an initial accelerated dose escalation phase of FR-α CAR-T cells followed by a standard 3 + 3 escalation phase. A split-dose approach is proposed to mitigate acute adverse events. Furthermore, infusion of bulk untransduced autologous peripheral blood lymphocytes (PBL) is proposed two days after CAR-T cell infusion at the lower dose levels of CAR-T cells, to suppress excessive expansion of CAR-T cells in vivo and mitigate toxicity.
authors.affiliation: Ovarian Cancer Research Center, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA. lknd@mail.med.upenn.edu
authors.forename: Lana E
authors.initials: LE
authors.lastname: Kandalaft
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D019264:Adoptive Transfer; D005240:Feasibility Studies; D005260:Female; D058975:Folate Receptor 1 / Q000276:immunology*; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D058975:Folate Receptor 1