title: CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma.
abstract: Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy for cancer. Selecting a target expressed in multiple-tumor types and that is required for tumor growth would widen disease indications and prevent immune escape caused by the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematologic and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human acute myeloid leukemia (AML) and multiple myeloma (MM) cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo. Finally, coexpressing a suicide gene enabled fast and efficient pharmacologic ablation of CD44v6-targeted T cells and complete rescue from hyperacute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.
authors.affiliation: Leukemia Immunotherapy Group, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Monica
authors.initials: M
authors.lastname: Casucci
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nicolis di Robilant
authors.forename: Laura
authors.initials: L
authors.lastname: Falcone
authors.forename: Barbara
authors.initials: B
authors.lastname: Camisa
authors.forename: Margherita
authors.initials: M
authors.lastname: Norelli
authors.forename: Pietro
authors.initials: P
authors.lastname: Genovese
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gentner
authors.forename: Fabiana
authors.initials: F
authors.lastname: Gullotta
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Massimo
authors.initials: M
authors.lastname: Bernardi
authors.forename: Magda
authors.initials: M
authors.lastname: Marcatti
authors.forename: Aurore
authors.initials: A
authors.lastname: Saudemont
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D045744:Cell Line, Tumor / Q000276:immunology / Q000637:transplantation; D003602:Cytotoxicity, Immunologic; D041722:Genes, Transgenic, Suicide; D006086:Graft vs Host Disease / Q000628:therapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015479:Leukemia, Myelomonocytic, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D017252:CD3 Complex; C112697:CD44v6 antigen; D018960:Hyaluronan Receptors; C569274:IL15 protein, human; C508605:IL7 protein, human; D019409:Interleukin-15; D015851:Interleukin-7; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins