title: Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b.
abstract: For adoptive T-cell therapy to be effective against solid tumors, tumor-specific T cells must be able to migrate to the tumor site. One requirement for efficient migration is that the effector cells express chemokine receptors that match the chemokines produced either by tumor or tumor-associated cells. In this study, we investigated whether the tumor trafficking of activated T cells (ATCs) bearing a chimeric antigen receptor specific for the tumor antigen GD2 (GD2-CAR) could be enhanced by forced coexpression of the chemokine receptor CCR2b, as this receptor directs migration toward CCL2, a chemokine produced by many tumors, including neuroblastoma. Neuroblastoma cell lines (SK-N-SH and SK-N-AS) and primary tumor cells isolated from 6 patients all secreted high levels of CCL2, but GD2-CAR transduced ATCs lacked expression of CCR2 (<5%) and migrated poorly to recombinant CCL2 or tumor supernatants. After retroviral transduction, however, ATCs expressed high levels of CCR2b (>60%) and migrated well in vitro. We expressed firefly luciferase in CCR2b-expressing ATCs and observed improved homing (>10-fold) to CCL2-secreting neuroblastoma compared with CCR2-negative ATCs. As a result, ATCs co-modified with both CCR2b and GD2-CAR had greater antitumor activity in vivo.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Craddock
authors.forename: An
authors.initials: A
authors.lastname: Lu
authors.forename: Adham
authors.initials: A
authors.lastname: Bear
authors.forename: Martin
authors.initials: M
authors.lastname: Pule
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Foster
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D019076:Transgenes / Q000235:genetics
chemical_list: D018932:Chemokine CCL2; D011948:Receptors, Antigen, T-Cell; D054390:Receptors, CCR2; D011993:Recombinant Fusion Proteins