Background: Cytokine-induced killer cells (CIKs) are an advanced therapeutic medicinal product (ATMP) that has shown therapeutic activity in clinical trials but needs optimization. We developed a novel strategy using CIKs from banked cryopreserved cord blood units (CBUs) combined with bispecific antibody (BsAb) blinatumomab to treat CD19+ malignancies. Methods: CB-CIKs were expanded in vitro and fully characterized in comparison with peripheral blood (PB)–derived CIKs. Results: CB-CIKs, like PB-CIKs, were mostly CD3+ T cells with mean 45% CD3+CD56+ and expressing mostly TCR(T cell receptor)αβ with a TH1 phenotype. CB-CIK cultures had, however, a larger proportion of CD4+ cells, mostly CD56−, as well as a greater proportion of naïve CCR7+CD45RA+ and a lower percentage of effector memory cells, compared with PB-CIKs. CB-CIKs were very similar to PB-CIKs in their expression of a large panel of co-stimulatory and inhibitory/exhaustion markers, except for higher CD28 expression among CD8+ cells. Like PB-CIKs, CB-CIKs were highly cytotoxic in vitro against natural killer (NK) cell targets and efficiently lysed CD19+ tumor cells in the presence of blinatumomab, with 30–60% lysis of target cells at very low effector:target ratios. Finally, both CB-CIKs and PB-CIKs, combined with blinatumomab, showed significant therapeutic activity in an aggressive PDX Ph+ CD19+ acute lymphoblastic leukemia model in NOD-SCID mice, without sign of toxicity or graft-versus-host disease. The improved expansion protocol was finally validated in good manufacturing practice conditions, showing reproducible expansion of CIKs from cryopreserved cord blood units with a median of 28.8 × 106 CIK/kg. Discussion: We conclude that CB-CIKs, combined with bispecific T-cell–engaging antibodies, offer a novel, effective treatment strategy for leukemia.
Cord blood–derived cytokine-induced killer cells combined with blinatumomab as a therapeutic strategy for CD19+ tumors / J. Golay, S. Martinelli, R. Alzani, S. Cribioli, C. Albanese, E. Gotti, B. Pasini, B. Mazzanti, R. Saccardi, A. Rambaldi, M. Introna. - In: CYTOTHERAPY. - ISSN 1465-3249. - 20:8(2018 Aug 01), pp. 1077-1088.
|Titolo:||Cord blood–derived cytokine-induced killer cells combined with blinatumomab as a therapeutic strategy for CD19+ tumors|
RAMBALDI, ALESSANDRO [Writing – Review & Editing]
|Parole Chiave:||adoptive therapy; bispecific antibody; cord blood; cytokine-induced killer; T lymphocytes; Immunology and Allergy; Immunology; Oncology; Genetics (clinical); Cell Biology; Transplantation; Cancer Research|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||1-ago-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.jcyt.2018.06.003|
|Appare nelle tipologie:||01 - Articolo su periodico|