ReviewClinical utility of natural killer cells in cancer therapy and transplantation
Introduction
The use of cellular immunotherapy has increased significantly over the past two decades. Discoveries in basic NK cell biology, together with growing clinical experience in the setting of hematopoietic cell transplantation (HCT), have placed NK cells along a trajectory of translational development. A deeper understanding of the interactions between active and suppressive immune cells in response to infected or malignantly transformed cells has been critical in the development of NK cell therapies for cancer. Major clinical advances include the use of cytokines to activate NK cells in vivo [1], [2], [3], use of monoclonal antibodies to redirect or enhance NK cell function [4], [5], [6], adoptive transfer of T cells or natural killer (NK) cells with anti-tumor activity [7], [8] and engineering adoptively transferred cells with artificial receptors specific for particular cell surface tumor antigens [9], [10], [11].
This review is focused upon the clinical utility of NK cells in patients with hematologic malignancies. We will review NK cell biology, the role of NK cells in hematopoietic cell transplantation, the rationale for using NK cells in cancer therapy, strategies to activate and expand NK cells and advances in adoptive transfer of autologous or allogeneic NK cells to treat cancer. Methods to optimize NK cell expansion and alloreactivity and limitations of current approaches are also considered, as are novel therapies intended to exploit unique properties of NK cells to advance cancer treatment. The ultimate goal of NK cell research is to transition from ex vivo isolation, expansion, and activation to optimizing therapeutic efficacy in appropriately selected patients.
Section snippets
Overview of NK cell phenotype, development, and receptors
Natural killer cells are innate lymphocytes with the capacity to recognize cells that have undergone viral infection or malignant transformation. They are so named for their “natural” ability to kill cancer cells without prior sensitization [12]. As demonstrated in patients lacking functional NK cells, they are important for defense against a variety of cancers and viral infections [13], [14], [15]. NK cells develop in the bone marrow [16] and then home to secondary lymphoid tissues where they
NK cell alloreactivity in allogeneic HSCT
Natural killer cells were initially recognized for their ability to lyse leukemic cells in mice [12], [65]. In 2002, Ruggeri et al. demonstrated superior disease-free survival in acute myologenous leukemia (AML) patients receiving bone marrow grafts from HLA-haploidentical donors who expressed KIR receptors which bound to MHC class I molecules absent in the host (i.e., KIR ligand mismatch in the graft versus host (GVH) direction) [66]. They also had a decreased incidence of graft versus host
NCI trials provide lymphodepleting platform for adoptive immunotherapy
In pioneering studies at the NCI, Rosenberg and colleagues infused melanoma and renal cell carcinoma patients with autologous peripheral blood cells treated ex vivo with IL-2. The product was enriched with NK cells and named “lymphocyte activated killer” (LAK) cells. High dose IL-2 was administered to patients after LAK infusions to promote their in vivo persistence and activity. In a subsequent trial, the NCI group adoptively transferred in vitro-expanded autologous tumor-infiltrating
Ex vivo expansion methods
Because NK cells comprise only 10–15% of PB lymphocytes and their isolation requires a costly selection process, several groups have developed methods to expand NK cells in vitro [100]. Initially, this approach used cytokines which proved successful but predisposed the NK cells to activation-induced cell death when in contact with the vascular endothelium [104]. IL-15, however, does not exert this effect on expanded NK cells. Instead, it promotes their survival and expansion [2]. Over the
Genetic modification and alternative sources of NK cell products
To overcome limitations of the donor-derived NK cell therapies, several groups have investigated alternative donor sources including UCB, NK cell lines and pluripotent stem cells. If cryopreservation can be optimized, the prompt availability of an off-the-shelf product represents a significant step forward. Additional advantages include the ability to perform preclinical testing and to select for donors based on favorable characteristics including optimal KIR-genotype [131].
UCB-derived NK cells
UBC progenitors
Conclusion
Clinical use of NK cells has been inspired by recognition of their potent anticancer activity. The studies discussed above provide a solid basis for development of future NK cell trials for cancer therapy while minimizing risks and toxicities (Fig. 1). Important questions remain to be answered including, most urgently, determination of minimum in vivo NK cell expansion needed for clinically effective anti-tumor activity. At present, outcomes involving NK cell expansion interventions remain
References (152)
- et al.
Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques
Blood
(2011) - et al.
Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy
Immunity
(2001) - et al.
Interleukin-2, interleukin-15, and their roles in human natural killer cells
Adv Immunol
(2005) - et al.
Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells
Blood
(2009) - et al.
Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56bright subset
Blood
(2013) - et al.
Human natural killer cell development and biology
Blood Rev
(2006) - et al.
Regulation of human NK-cell cytokine and chemokine production by target cell recognition
Blood
(2010) - et al.
IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation
Immunity
(1998) - et al.
Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors
Immunity
(1997) - et al.
Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia
Blood
(2009)