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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Available from: Mobin Karimi, Oct 08, 2015
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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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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment option for high-risk hematological malignancies, and may also be offered to patients with solid malignancies refractory to conventional therapies. In case of patients' relapse, refractory tumor cells may then be targeted by cellular therapy-based combination strategies. Here, we investigated the potential of small molecule IAP (SMAC mimetic) BV6 in increasing cytokine-induced killer (CIK) cell-mediated cytotoxicity against different tumor targets. Four-hour pre-incubation with 2.5 μMol BV6 moderately enhanced CIK cell-mediated lysis of hematological (H9, THP-1, and Tanoue) and solid malignancies (RH1, RH30, and TE671). However, BV6 also increased apoptosis of non-malignant cells like peripheral blood mononuclear cells and most notably had an inhibitory effect on immune cells potentially limiting their cytotoxic potential. Hence, cytotoxicity increased in a dose-dependent manner when BV6 was removed before CIK cells were added to tumor targets. However, cytotoxic potential was not further increasable by extending BV6 pre-incubation period of target cells from 4 to 12 h. Molecular studies revealed that BV6 sensitization of target cells involved activation of caspases. Here, we provide evidence that SMAC mimetic may sensitize targets cells for CIK cell-induced cell death. However, BV6 also increased apoptosis of non-malignant cells like CIK cells and peripheral mononuclear cells. These findings may therefore be important for cell- and small molecule IAP-based combination therapies of resistant cancers after allogeneic HSCT.
    Frontiers in Pediatrics 07/2014; 2:75. DOI:10.3389/fped.2014.00075
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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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    ABSTRACT: Donor cell engraftment is critical for the success of allogeneic bone marrow transplants. Graft failure is a result of donor cells either failing to engraft initially or being eliminated at later time points. Donor cell engraftment is facilitated by donor T cells, which eliminate residual host hemato-lymphoid effector cells such as NK cells and T cells. We aimed to explore the role of host hematopoietic cell derived IL-12 on donor cell engraftment in a murine model of BMT. We established radiation chimeras by transplanting C57BL6/J (B6) mice with BM from either congenic B6 mice or IL-12p40 KO mice. These WT [rightwards arrow] WT or IL-12 KO [rightwards arrow] WT chimeras then underwent a secondary transplant with allogeneic (FVB) BM. Survival, engraftment, donor T cell expansion, cytokine production by donor T cells, as well as expression of stimulatory markers on donor T cells was analyzed. Mice whose residual host hematopoietic cells were capable of producing IL-12 had modestly higher survival, and significantly higher donor T cell and erythroid engraftment. We have also found that an increased number of donor T cells in IL-12 KO [rightwards arrow] WT chimeras have a regulatory phenotype, expressing FoxP3, producing lower levels of TNF-alpha, higher levels of IL-10, and expressing higher levels of ICOS as well as PD-1 on CD4+ T cells. To our knowledge, this is the first report of a beneficial role of IL-12 production by host cells in the context of bone marrow engraftment in a murine model of BMT. These findings support the clinical use of exogenous IL-12 for use in settings where graft failure is of concern.
    Journal of Hematology & Oncology 02/2014; 7(1):16. DOI:10.1186/1756-8722-7-16 · 4.81 Impact Factor
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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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    ABSTRACT: Stereotactic body radiation therapy (SBRT) concentrates radiation to a predefined target, affecting all the cells within it. Adoptive immunotherapy is not restricted by the major histocompatibility complex (MHC) in recognizing and eliminating target cells. We investigated the effects of the combined modality of SBRT and adoptive immunotherapy on patients with advanced malignant tumors. The database of 316 patients with 845 tumors who underwent SBRT between April, 2010 and February, 2012 was retrospectively reviewed. Of the 316 patients, 145 received biological immunotherapy and were assigned into the observation group, whereas the remaining patients constituted the control group. Patients in the two groups were recorded on efficacy assessment, Karnofsky performance status (KPS), cell phenotype expression level in vitro and the percentages of lymphocyte subsets and ratio of CD4(+)/CD8(+) lymphocytes in the peripheral blood. Following treatment, the total effectiveness [complete response (CR) + partial response (PR)], the KPS score, the percentages of lymphocyte subsets and the CD4(+)/CD8(+) lymphocyte ratio in the observation group were higher compared to those in the control group, with a statistically significant difference (P<0.05). The expression of CD3(+) and CD3(+)CD56(+) cytokine-induced killer (CIK) cells were increased from 56.76±4.54% and 11.32±2.96% to 94.67±4.46% and 32.65±1.12%, respectively, when cultured in vitro (P<0.01). The percentages of lymphocyte subsets and the CD4(+)/CD8(+) lymphocyte ratio were significantly increased compared to prior to treatment in the observation group (P<0.05). SBRT combined with adoptive immunotherapy may be a novel therapeutic option for patients with advanced malignant tumors.
    Molecular and Clinical Oncology 09/2013; 1(5):925-929. DOI:10.3892/mco.2013.157
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