Abstract
Recent clinical studies suggest that adoptive transfer of donor-derived natural killer (NK) cells may improve clinical outcome in hematological malignancies and some solid tumors by direct anti-tumor effects as well as by reduction of graft versus host disease (GVHD). NK cells have also been shown to enhance transplant engraftment during allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. The limited ex vivo expansion potential of NK cells from peripheral blood (PB) or umbilical cord blood (UCB) has however restricted their therapeutic potential. Here we define methods to efficiently generate NK cells from donor-matched, full-term human placenta perfusate (termed Human Placenta-Derived Stem Cell, HPDSC) and UCB. Following isolation from cryopreserved donor-matched HPDSC and UCB units, CD56+CD3− placenta-derived NK cells, termed pNK cells, were expanded in culture for up to 3 weeks to yield an average of 1.2 billion cells per donor that were >80% CD56+CD3−, comparable to doses previously utilized in clinical applications. Ex vivo-expanded pNK cells exhibited a marked increase in anti-tumor cytolytic activity coinciding with the significantly increased expression of NKG2D, NKp46, and NKp44 (p < 0.001, p < 0.001, and p < 0.05, respectively). Strong cytolytic activity was observed against a wide range of tumor cell lines in vitro. pNK cells display a distinct microRNA (miRNA) expression profile, immunophenotype, and greater anti-tumor capacity in vitro compared to PB NK cells used in recent clinical trials. With further development, pNK may represent a novel and effective cellular immunotherapy for patients with high clinical needs and few other therapeutic options.
Highlights
The critical role of natural killer (NK) cells in the defense against cancer and virus infection has been increasingly appreciated since they were first discovered in mice more than 30 years ago (Herberman et al, 1975a,b)
Several clinical studies have convincingly demonstrated that adoptive transfer of NK cells isolated from peripheral blood (PB) of haploidentical donors can be successfully used for immunotherapy in acute myeloid leukemia (AML) patients (Miller et al, 2005; Rubnitz et al, 2010; Curti et al, 2011)
We have described, for the first time, that human placenta-derived stem cells (HPDSC) combined with www.frontiersin.org donor-matched umbilical cord blood (UCB), are a novel and rich source of placentaderived NK (pNK) cells
Summary
The critical role of natural killer (NK) cells in the defense against cancer and virus infection has been increasingly appreciated since they were first discovered in mice more than 30 years ago (Herberman et al, 1975a,b). Clinical studies exploring the biological activities of NK cells in the treatment of malignant disease and during allogeneic hematopoietic stem cell transplantation (HSCT) have provided promising results. Transplant studies have suggested alloreactive NK cells could mediate potent anti-leukemia effects without causing graft versus host disease (GVHD). In human leukocyte antigen (HLA)-mismatched, haploidentical allogeneic stem cell transplants (SCT), NK alloreactivity was associated with a higher rate of survival, a lower rate of relapse, and treatment related mortality post transplantation (Ruggeri et al, 1999, 2002; Velardi et al, 2002). Several clinical studies have convincingly demonstrated that adoptive transfer of NK cells isolated from peripheral blood (PB) of haploidentical donors can be successfully used for immunotherapy in acute myeloid leukemia (AML) patients (Miller et al, 2005; Rubnitz et al, 2010; Curti et al, 2011). There is a need to overcome these challenges and enable a NK cell-based anti-tumor strategy in the clinic
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