title: Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells.
abstract: T cells expressing a chimeric antigen receptor (CAR) can produce dramatic results in lymphocytic leukemia patients; however, therapeutic strategies for myeloid leukemia remain limited. Folate receptor β (FRβ) is a myeloid-lineage antigen expressed on 70% of acute myeloid leukemia (AML) patient samples. Here, we describe the development and evaluation of the first CARs specific for human FRβ (m909) in vitro and in vivo. m909 CAR T cells exhibited selective activation and lytic function against engineered C30-FRβ as well as endogenous FRβ(+) AML cell lines in vitro. In mouse models of human AML, m909 CAR T cells mediated the regression of engrafted FRβ(+) THP1 AML in vivo. In addition, we demonstrated that treatment of AML with all-trans retinoic acid (ATRA) enhanced FRβ expression, resulting in improved immune recognition by m909 CAR T cells. Because many cell surface markers are shared between AML blasts and healthy hematopoietic stem and progenitor cells (HSCs), we evaluated FRβ expression and recognition of HSCs by CAR T cells. m909 CAR T cells were not toxic against healthy human CD34(+) HSCs in vitro. Our results indicate that FRβ is a promising target for CAR T-cell therapy of AML, which may be augmented by combination with ATRA.
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, and.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Lynn
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, and.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Poussin
authors.affiliation: Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Anna
authors.initials: A
authors.lastname: Kalota
authors.affiliation: Protein Interactions Section, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD;
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN; and.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
authors.affiliation: Protein Interactions Section, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD;
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, and Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D058976:Folate Receptor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D050506:Mutant Chimeric Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D058976:Folate Receptor 2; D050506:Mutant Chimeric Proteins; D011948:Receptors, Antigen, T-Cell