title: Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma.
abstract: The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01 to re-direct autologous CD8(+) T cells towards NY-ESO-1(+) myeloma cells. These re-directed T cells specifically lysed NY-ESO-1(157-165)/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7(-) re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7(+) memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1(157-165)/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo.
authors: Department of Oncology, University Hospital Zurich, Zürich, Switzerland.
authors: P C
authors: PC
authors: Schuberth
authors: G
authors: G
authors: Jakka
authors: S M
authors: SM
authors: Jensen
authors: A
authors: A
authors: Wadle
authors: F
authors: F
authors: Gautschi
authors: D
authors: D
authors: Haley
authors: S
authors: S
authors: Haile
authors: A
authors: A
authors: Mischo
authors: G
authors: G
authors: Held
authors: M
authors: M
authors: Thiel
authors: M
authors: M
authors: Tinguely
authors: C B
authors: CB
authors: Bifulco
authors: B A
authors: BA
authors: Fox
authors: C
authors: C
authors: Renner
authors: U
authors: U
authors: Petrausch
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D000951:Antigens, Neoplasm; C515370:CCR7 protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D054400:Receptors, CCR7; C504237:peptide NY-ESO-1 157-165; D007371:Interferon-gamma