Cytotherapy 2018 08 7;20(8):1077-1088. Epub 2018 Aug 7.
Center of Cellular Therapy "G. Lanzani", Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy. Electronic address:
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% CD3CD56 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 CCR7CD45RA 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 × 10 CIK/kg.
Discussion: We conclude that CB-CIKs, combined with bispecific T-cell-engaging antibodies, offer a novel, effective treatment strategy for leukemia.