Ex vivo allogeneic stimulation significantly improves expansion of cytokine-induced killer cells without increasing their alloreactivity across HLA barriers.
Cytokine-induced killer cells (CIKs) are ex vivo expanded T-NK lymphocytes capable of HLA-unrestricted antitumor activity. CIKs are promising candidates for adoptive cancer immunotherapies; they can be generated and infused in autologous settings of cancer patients, or from donors, after allogeneic hematopoietic cell transplant. Ex vivo expansion rates of CIKs are greatly variable among patients, with consequent potential clinical limitations for "poor expanders." We compared the standard expansion protocol with a new one, which included the timed addition of irradiated allogeneic peripheral blood mononuclear cells. Our hypothesis is that allogeneic stimulation might provide CIK cells with a proliferative boost and simultaneously decrease their alloreactivity versus third parties, if HLA-mismatched from the allogeneic stimulators. Allo-stimulated CIKs (AS-CIK) reached significantly higher expansion rates compared with standard controls, regardless if generated form healthy donors (131- vs. 32-fold) or cancer patients (117- vs. 14-fold). The expansion of the CD3CD56 subset was 2243-fold for AS-CIKs compared with 362 for standard CIKs. AS-CIKs efficiently killed osteosarcoma targets in vitro, results were comparable with that of standard CIKs. Standard and AS-CIKs did not show differences in phenotype and telomere length. The alloreactivity of AS-CIKs against third party HLA-mismatched peripheral blood mononuclear cells was reduced compared with standard CIKs (37% vs. 23%). In conclusion, alloreactivity of CIK cells may be exploited enhancing their final ex vivo expansion. In clinical perspective these findings may facilitate the extension of CIK-based immunotherapy to larger numbers of patients and, translated into hematopoietic cell transplant settings, contribute to reduce the risk of graft versus host disease in the hypothesis of infusions across HLA barriers.
Department of Oncological Sciences, Laboratory of Cell Therapy of Cancer, University of Torino Medical School, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy.
Maja
M
Todorovic
Giulia
G
Mesiano
Loretta
L
Gammaitoni
Valeria
V
Leuci
Lidia
L
Giraudo Diego
Cristina
C
Cammarata
Noela
N
Jordaney
Fabrizio
F
Carnevale-Schianca
Susanna
S
Gallo
Franca
F
Fagioli
Wanda
W
Piacibello
Angela Rita
AR
Elia
Ymera
Y
Pignochino
Carmine
C
Dell'aglio
Giovanni
G
Grignani
Alessandro
A
Cignetti
Massimo
M
Aglietta
Dario
D
Sangiolo
D001859:Bone Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017252:CD3 Complex / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D049109:Cell Proliferation; D002478:Cells, Cultured; D055612:Cytokine-Induced Killer Cells / Q000276:immunology* / Q000637:transplantation; D003602:Cytotoxicity, Immunologic; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007114:Immunization; D016219:Immunotherapy, Adoptive; D007519:Isoantigens / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D012516:Osteosarcoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*
D017252:CD3 Complex; D019002:CD56 Antigen; D006680:HLA Antigens; D007519:Isoantigens