title: T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect.
abstract: Relapse of B-lineage acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem cell transplantation (HSCT) commonly results from the failure of a graft-versus-leukemia (GVL) effect to eradicate minimal residual disease. Augmenting the GVL effect by the adoptive transfer of donor-derived B-ALL-specific T-cell clones is a conceptually attractive strategy to decrease relapse rates without exacerbating graft-versus-host disease (GVHD). Toward this end, we investigated whether a genetic engineering approach could render CD8(+) cytotoxic T lymphocytes (CTLs) specific for tumor cells that express the B-cell lineage cell surface molecule CD19. This was accomplished by the genetic modification of CTLs to express a chimeric immunoreceptor composed of a CD19-specific single-chain immunoglobulin extracellular targeting domain fused to a CD3-zeta intracellular signaling domain. CD19-redirected CTL clones display potent CD19-specific lytic activity and chimeric immunoreceptor-regulated cytokine production and proliferation. Because B-ALL cells can evade T-cell/natural killer- cell recognition by down-regulation of cell surface accessory molecules that participate in the formation of a functional immunologic synapse, we compared the CD19-specific effector function of genetically modified CD8(+) CTLs toward CD19(+) cells with disparate levels of intercellular adhesion molecule 1 (ICAM-1), leukocyte function-associated antigen 1 (LFA-1), and LFA-3. We observed that recognition of B-lineage tumor lines by CD19-specific CTLs was not impaired by low levels of ICAM-1, LFA-1, and LFA-3 cell surface expression, a functional attribute that is likely a consequence of our high-affinity CD19-specific chimeric immunoreceptor. Furthermore, the CD19-specific CTLs could lyse primary B-ALL blasts. These preclinical observations form the basis for implementing clinical trials using donor-derived CD19-specific T-cell clones to treat or prevent relapse of B-ALL after allogeneic HSCT.
authors.affiliation: Division of Pediatric Hematology/Oncology, Beckman Research Institute and City of Hope National Medical Center, Duarte, CA 91010, USA. lcooper@coh.org
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
authors.forename: Max S
authors.initials: MS
authors.lastname: Topp
authors.forename: Lisa Marie
authors.initials: LM
authors.lastname: Serrano
authors.forename: Sergio
authors.initials: S
authors.lastname: Gonzalez
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Chang
authors.forename: Araceli
authors.initials: A
authors.lastname: Naranjo
authors.forename: Christine
authors.initials: C
authors.lastname: Wright
authors.forename: Leslie
authors.initials: L
authors.lastname: Popplewell
authors.forename: Andrew
authors.initials: A
authors.lastname: Raubitschek
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
mesh_terms: D019264:Adoptive Transfer; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000276:immunology / Q000628:therapy; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D018968:CD58 Antigens / Q000032:analysis; D002999:Clone Cells / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D015870:Gene Expression; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012008:Recurrence; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000276:immunology*; D014162:Transfection
chemical_list: D018941:Antigens, CD19; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D018968:CD58 Antigens; D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1