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 (pts) with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT). However, graft vs 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 upregulation of the NK cell receptor, NKG2D (CD314). CIK cells are non-MHC restricted, and NKG2D dependent in target recognition and cytotoxicity. We explored the feasibility of ex vivo expansion of allogeneic CIK cells for pts with relapsed hematologic malignancies after allogeneic HCT. Eighteen patients with a median age of 53 years (range 20–69) received CIK cell infusions based on CD3+cells/kg at escalating doses of 1×107 (n=4), 5×107 (n=6) and 1×108 (n=8). The median expansion of CD3+ cells was 12 fold (range 4–91 fold). CD3+CD56+ cells represented a median of 11% (range 4–44%) of the harvested cells with a median 31 fold (range, 7–515 fold) expansion. Median CD3+CD314+ 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, grades I–II, were seen in 2 patients and 1 patient has limited chronic GVHD. After a median followup of 20 months (range 1–69 months) from CIK infusion, the median overall survival was 28 months and 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 transplantation to relapse. This form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD supporting further investigation as an upfront modality to enhance GVT responses in high risk patient populations.

Feasibility of IL-15-activated cytokine-induced killer cell infusions after haploidentical stem cell transplantation

“…Thus far, CIK cell infusions had only been tested after matched-donor allogeneic transplantation. 4,5,10 Our data demonstrate a similar safety and feasibility of CIK cell therapy from haploidentical donors.…”

“…Also other groups have reported limited efficacy of CIK cell infusions. 4,10 In our patients, CIK cell therapy may not have reached its full potential, as it was initiated during advanced disease. 1 In conclusion, these findings demonstrate the safety and feasibility of haploidentical CIK cell infusions, albeit in a small number of heterogeneous, pediatric patients, who in part had also received concomitant antitumor therapy.…”

Identification of a protein associated with the activity of cytokine‑induced killer cells

“…Lymphocytes were separated and cultured as reported by Pan et al (12), and Laport et al (13) with certain modifications. Equivalent volumes of peripheral blood and 0.9% physiological saline were mixed followed with ficoll gradient separation (LymphoPrep; PAA Laboratories; GE Healthcare, Chicago, IL, USA).…”

CIK cells – current status, clinical perspectives and future prospects – the good news

“…These trials have reported efficacy with well-tolerated toxicities in the treatment of patients with metastatic diseases, lymphoma and acute leukemia. For example, a recent Phase I dose-escalation trial by Negrin's group with allogeneic CIK cell infusions in patients with relapsed hematologic malignancies reached the planned maximum cell dose of 1 Â 10 8 CD3 + cells/kg as the maximum tolerated dose with low incidence of graft-versus-host disease (GVHD) paralleled to that reported in preclinical models [2] and provides further rationale of the clinical use of CIK cells.…”