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

International Immunology, Jul 2008

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.

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

Dario Sangiolo 1 2 5 Emanuela Martinuzzi 0 1 Maja Todorovic 1 Katiuscia Vitaggio 1 2 Antonella Vallario 1 Noela Jordaney 5 Fabrizio Carnevale-Schianca 5 Antonio Capaldi 5 Massimo Geuna 0 Laura Casorzo 4 Richard A. Nash 3 Massimo Aglietta 2 5 Alessandro Cignetti 1 0 Laboratory of Clinical and Experimental Cytometry 1 Laboratory of Cancer Immunology 2 Department of Oncological Sciences, University of Torino Medical School , Torino, Italy 3 Fred Hutchinson Cancer Research Center and University of Washington Medical School , Seattle, WA, USA 4 Unit of Pathology, Institute for Cancer Research and Treatment , Candiolo, Torino, Italy 5 Division of Medical Oncology 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 CD31/CD561 cell fraction and alloreactivity versus HLA-mismatched PBMC was restricted to the CD31/CD562 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 CD31/CD562 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. Introduction Cytokine-induced killer (CIK) cells are a subset of T lymphocytes with a NK T cell (NKT) phenotype expressing both the CD3 and the CD56 markers. CIK cells are mostly CD8+, express a heterogeneous TCR repertoire, are CD1d independent and can be reproducibly expanded in vitro from bone marrow or PBMC over a 3-week time period (14). CIK cells are capable of a broad MHC-unrestricted anti-tumor activity against both syngeneic and allogeneic hematological malignancies, as documented both in vitro and in vivo by murine models (1, 4, 5). In pre-clinical studies conducted to date, lymphoma cell lines and fresh leukemic blasts have been the main tumor targets (1, 5, 6). Limited data are available on the efficacy of CIK cells against solid tumors, although efficient killing 842 CIK alloreactivity across major HLA barriers of hepatocarcinoma by conventional CIK and of ovarian carcinoma by CIK redirected against the tumor by a bispecific antibody has been published (79). The mechanism of tumor killing by CIK cells is perforin mediated but, to date, it is not completely known which molecules are involved in tumor recognition (10). An important role is played by NKG2D homodimer, which mediates the interaction between CIK cells and tumor targets expressing NKG2D ligands (11). Two phase I clinical trials reported the successful ex vivo expansion and reinfusion of CIK cells from patients with refractory malignant lymphoma and hepatocellular carcinoma without any relevant toxicity and with few (3/22) but significant clinical responses (12, 13). Allogeneic hematopoietic cell transplantation (HCT) is an established therapy for hematological malignancies (14) and more recently studies of HCT after non-myeloablative conditioning (NMT) have been extended to the field of solid tumors (1519). Most of the therapeutic effect of NMT depends on an immune response of allogeneic donor T cells to recipient malignant cells, referred to as a graft versus tumor (GVT) effect. NMT has shown to reduce regimen-related toxicities in comparison with conventional myeloablative conditioning but graft-versus-host disease (GVHD) and disease progression remain significant challenges. The beneficial allogeneic GVT effect may be improved by the infusion of donor lymphocytes, even if the risk of severe GVHD remains the major drawback (2023). In the allogeneic HCT setting, the GVHD potential of CIK cells was found to be very low in mice models (1, 4, 5). This makes CIK cells an intriguing alternative to bulk donor lymphocytes infusion (DLI), especially when donor and recipient ha (...truncated)


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Dario Sangiolo, Emanuela Martinuzzi, Maja Todorovic, Katiuscia Vitaggio, Antonella Vallario, Noela Jordaney, Fabrizio Carnevale-Schianca, Antonio Capaldi, Massimo Geuna, Laura Casorzo, Richard A. Nash, Massimo Aglietta, Alessandro Cignetti. Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers, International Immunology, 2008, pp. 841-848, 20/7, DOI: 10.1093/intimm/dxn042