Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers

Abstract

Donor-derived cytokine-induced killer (CIK) can be infused as adoptive immunotherapy after hematopoietic cell transplant (HCT). Promising results were recently reported in HLA-identical HCT, where mild grafts versus host (GVH) events were observed. To extend this strategy across major HLA barriers (e.g. HLA-haploidentical HCT), further studies on CIK cells' alloreactivity are needed. We hypothesized that alloreactivity and anti-tumor activity of CIK cells segregate within two different cell subsets and could consequently be separated according to CD56 and CD3 expression. We tested CIK cells expanded from seven patients who underwent HCT as treatment of metastatic colorectal cancer. We found that CIK cells maintained their alloreactivity across major HLA barriers when tested as bulk population; after CD56-positive selection, anti-tumor activity was restricted to the CD3+/CD56+ cell fraction and alloreactivity versus HLA-mismatched PBMC was restricted to the CD3+/CD56- cell fraction. Bulk CIK cells from engrafted patients did not exhibit alloreactivity in response to host- or donor-derived PBMC, confirming their low potential for GVH across minor HLA barriers. Moreover, we tested if CIK cells expanded from engrafted patients after HCT were as effective as donor-derived ones and could be considered as an alternative option. The expansion rate and tumor cell killing was comparable to that observed in sibling donors. In conclusion, depletion of CD3+/CD56- cells might reduce the risk of GVH without affecting the tumor-killing capacity and could help extending CIK infusions across major HLA barriers. Engrafted patients after HCT could also be considered as an effective alternative option to donor-derived CIK cells.

Effect of Chinese Medicine XIAOJI Decoction Combined with Platinum-Based Chemotherapy and Transfusion of Cytokine-Induced Killer Cells in Patients with Stage III B/IV Non-Small Cell Lung Cancer

“…CIK cells generated by in vitro expansion of peripheral blood lymphocytes (PBLs) using anti-CD3 antibodies, IL-2 and IFN-γ. + T cells depends on binding to and formation of cellular conjugation with tumor cells, and production of perforin and granzyme B, two cytolytic factors, but not major histocompatibility complex (MHC) [24]. As we all know, most of the tumor cells do not express MHC or human leukocyte antigen (HLA), which helped tumor cells to escape from the immune system.…”

A clinical study of cytokine-induced killer cells for the treatment of refractory lymphoma

“…The CIK cells were diluted with 100 ml saline and transfused back to the patients, 1/3 to 4 fractions at a time, once every 2-3 days. The cell count at each transfusion was >10 9 . Deproteinized nutrition cell extract of calf blood and >2,000 ml fluid were administered following transfusion.…”

“…CIK cells have been found to reduce acquisition of homing molecules required for the entry of cells into inflamed graft-versus-host disease (GVHD) target organs, causing GVHD (8). CIK cells can also be an alternative to bulk donor lymphocyte infusion (DLI) (9).…”

Culture and differentiation of cytokine-induced killer cells from umbilical cord blood-derived mononuclear cells

“…The qualifier "cytokine-induced killer" indicates that they are generated via administration of cytokines during in vitro culture (Arafar, 2014;Linn and Hui, 2010). Cells which have the most potential effector function in CIK culture coexpress CD3 and CD56 surface molecules; possess a potent, MHC-unrestricted tumor-killing ability; and significantly reduced alloreactivity (Sangiolo et al, 2008). CIK cells recognize tumor cells through the binding of CIK NKG2D receptors with tumor cell ligands such as MHC class I polypeptide-related sequences A and B (MICA and MICB); they then facilitate tumor cytolysis through secretion of perforin and granzyme degranulators (Mehta et al, 1995;Pievani et 461 Culture and differentiation of cytokine-induced killer cells al., 2011; Schmidt-Wolf et al, 1993).…”