title: Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation.
abstract: Donor leukocyte infusions induce remissions in some patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT); however, graft-versus-host disease (GVHD) remains the major complication of this strategy. Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes that express the CD3(+)CD56(+) phenotype and show marked up-regulation of the natural killer cell receptor NKG2D (CD314). CIK cells are non-major histocompatibility complex-restricted and NKG2D-dependent in target recognition and cytotoxicity. We explored the feasibility of ex vivo expansion of allogeneic CIK cells in patients with relapsed hematologic malignancies after allogeneic HCT. Eighteen patients (median age, 53 years; range, 20-69 years) received CIK cell infusions at escalating doses of 1 × 10(7) CD3(+) cells/kg (n = 4), 5 × 10(7) CD3(+) cells/kg (n = 6), and 1 × 10(8) CD3(+) cells/kg (n = 8). The median expansion of CD3(+) cells was 12-fold (range, 4- to 91-fold). CD3(+)CD56(+) cells represented a median of 11% (range, 4%-44%) of the harvested cells, with a median 31-fold (range, 7- to 515-fold) expansion. Median CD3(+)CD314(+) cell expression was 53% (range, 32%-78%) of harvested cells. Significant cytotoxicity was demonstrated in vitro against a panel of human tumor cell lines. Acute GVHD grade I-II was seen in 2 patients, and 1 patient had limited chronic GVHD. After a median follow-up of 20 months (range, 1-69 months) from CIK infusion, the median overall survival was 28 months, and the median event-free survival was 4 months. All deaths were due to relapsed disease; however, 5 patients had longer remissions after infusion of CIK cells than from allogeneic HCT to relapse. Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD, supporting further investigation as an upfront modality to enhance graft-versus-tumor responses in high-risk patient populations.
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University School of Medicine, 300 Pastaur Drive, Stanford, CA 94305, USA. glaport@stanford.edu
authors.forename: Ginna G
authors.initials: GG
authors.lastname: Laport
authors.forename: Kevin
authors.initials: K
authors.lastname: Sheehan
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.forename: Randall
authors.initials: R
authors.lastname: Armstrong
authors.forename: Ruby M
authors.initials: RM
authors.lastname: Wong
authors.forename: Robert
authors.initials: R
authors.lastname: Lowsky
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Johnston
authors.forename: Judith A
authors.initials: JA
authors.lastname: Shizuru
authors.forename: David
authors.initials: D
authors.lastname: Miklos
authors.forename: Sally
authors.initials: S
authors.lastname: Arai
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Benjamin
authors.forename: Wen-Kai
authors.initials: WK
authors.lastname: Weng
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
mesh_terms: D000328:Adult; D000368:Aged; D046528:Chimerism; D055612:Cytokine-Induced Killer Cells / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology; D019337:Hematologic Neoplasms / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D014184:Transplantation, Homologous / Q000009:adverse effects; D055815:Young Adult