Nishimura R, Baker J, Beilhack A, Zeiser R, Olson JA, Sega EI, Karimi M, Negrin RSIn vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood 112: 2563-2574

Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, CA 94305, USA.
Blood (Impact Factor: 10.45). 07/2008; 112(6):2563-74. DOI: 10.1182/blood-2007-06-092817
Source: PubMed


Cytokine-induced killer (CIK) cells are ex vivo-expanded T lymphocytes expressing both natural killer (NK)- and T-cell markers. CIK cells are cytotoxic against autologous and allogeneic tumors. We previously showed that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD). However, the precise mechanism of reduced GVHD is not fully understood. Therefore, we evaluated the trafficking and survival of luciferase-expressing CIK cells in an allogeneic bone marrow transplant model. The initial trafficking patterns of CIK cells were similar to conventional T cells that induced GVHD; however, CIK cells infiltrated GVHD target tissues much less and transiently. CIK cells accumulated and persisted in tumor sites, resulting in tumor eradication. We evaluated different properties of CIK cells compared with conventional T cells, demonstrating a slower division rate of CIK cells, higher susceptibility to apoptosis, persistent increased expression of interferon gamma (IFN-gamma), and reduced acquisition of homing molecules required for entry of cells into inflamed GVHD target organs that lack expression of NKG2D ligands recognized by CIK cells. Due to these properties, allogeneic CIK cells had reduced expansion and caused less tissue damage. We conclude that CIK cells have the potential to separate graft-versus-tumor effects from GVHD.

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    • "Remarkably, not only BV6 treatment, but also the presence of target cells alone, induced apoptosis in CIK cells. Accordingly, Nishimura et al. (55) demonstrated high percentages of early apoptotic cells in mice transplanted with CIK cells alone, suggesting that CIK cells per se demonstrated limited life span and increased susceptibility to apoptosis. Our results confirmed high expression levels of active caspase-3 fragments as a sign of activated apoptosis pathways in CIK cells being in contact with tumor cells. "
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    • "Congenic strains expressing CD90.1 and CD45.2 on a B6 (H-2Kb) background (BA), and CD90.1, CD45.2 on a B10.BR (H-2Kk) background (BA.B10) were backcrossed 10 generations to the parental strain and bred at Emory University Animal Care Facility (Atlanta, GA, USA). The luc + transgenic mice (FVB-L2G85) on the FVB background were a gift from Dr. Robert Negrin (Stanford University) [38]. All transplant recipients were monitored daily for survival. "
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    • "CIKs possess versatile antitumor advantages, including easier generation from T cells, more potent cytotoxicity against tumors and more enhanced in vivo proliferation potency (6–8). Furthermore, CIK cells were reported to have minimal cytotoxic activity against normal marrow or hematopoietic cells (9). We conducted a randomized controlled trial to assess whether adoptive immunotherapy with CIK cells may be beneficial when used as adjuvant therapy with SBRT in the treatment of malignancies. "
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