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International Immunology Advance Access originally published online on May 9, 2008
International Immunology 2008 20(7):841-848; doi:10.1093/intimm/dxn042
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

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 Sangiolo1,2,4, Emanuela Martinuzzi2,3, Maja Todorovic2, Katiuscia Vitaggio1,2, Antonella Vallario2, Noela Jordaney4, Fabrizio Carnevale-Schianca4, Antonio Capaldi4, Massimo Geuna3, Laura Casorzo5, Richard A. Nash6, Massimo Aglietta1,4 and Alessandro Cignetti2

1 Department of Oncological Sciences, University of Torino Medical School, Torino, Italy
2 Laboratory of Cancer Immunology
3 Laboratory of Clinical and Experimental Cytometry
4 Division of Medical Oncology
5 Unit of Pathology, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy
6 Fred Hutchinson Cancer Research Center and University of Washington Medical School, Seattle, WA, USA

Correspondence to: A. Cignetti; E-mail: alex.cignetti{at}ircc.it

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.

Keywords: DLI, GVHD, GVT, haploidentical transplant

Transmitting editor: T. Takai

Received 29 October 2007, accepted 8 April 2008.


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