Natural killer cell therapy for cancer: delivering on a promise

D espite recent advances in multidisciplinary therapy and supportive care for children and adults with cancer, cure rates remain unacceptably low. The limitations of current therapies, coupled with improved understanding of cancer genetics and immunology, have led investigators to pursue innovative biologic therapies with non–crossresistant mechanisms of action and no overlapping toxicities. Cancer immunotherapy is predicated on augmenting different aspects of the immune response and has been explored throughout medical history. Natural killer (NK) cells, specifically, have been known to be capable of killing malignant cells without prior sensitization since their initial description in 1975, although their role in human cancer prevention at that time was less clear. Decades later, a large, prospective study that followed healthy adults in Japan provided compelling evidence that endogenous NK-cell activity is important for human cancer surveillance. In this study, men and women with higher levels of natural cytotoxicity by peripheral blood NK cells were at significantly decreased risk of developing cancer. Allogeneic hematopoietic stem cell transplantation (HCT) was the first widely accepted form of immunotherapy, where graft-versus-tumor effects provide anticancer benefit beyond those afforded by high-dose chemotherapy or radiation. Despite this advantage, allogeneic HCT remains a treatment with considerable treatment-related morbidity, especially graft-versus-host disease (GVHD), which is mediated by donor T lymphocytes. Unlike T cells, NK cells do not produce GVHD. In contrast, NK cells can attack tumor cells and protect against GVHD simultaneously. Valiante and Parham initially predicted NK-cell alloreactivity in clinical transplantation based on donor killer immunoglobulin-like receptor (KIR) and host HLA. Since that time, the importance of KIR typing in donor selection has been increasingly recognized. Favorable NK-cell activity has been observed in autologous HCT as well. Adoptive NK-cell therapy without prior HCT represents a promising new frontier in cancer immunotherapy. Human NK cells are a diverse and complex subset of lymphocytes that constitute a critical component of the innate immune system. Increasing evidence points to a role for NK cells in various phases of the adaptive immune response as well. These diverse functions are governed by a complex yet rapid integration of activating and inhibitory signals, especially those through KIR and HLA interactions. Among other important functions, NK cells kill transformed or virally infected cells through directed degranulation of potent cytolytic granules or expression of death receptor ligands. Target cell killing occurs without the antecedent antigen priming required by T cells. To overcome the NK-cell dysfunction commonly observed in cancer patients, Miller and colleagues first described the successful adoptive transfer of healthy donor NK-enriched cell products in the nontransplant setting. In that study, 19 adults with acute myelogenous leukemia received a short regimen of immunosuppressive chemotherapy followed by a cell product that was enriched to approximately 40% NK cells. More than half of the patients had detectable cell engraftment, and several patients entered complete remission. Other investigators have since shown allogeneic NK-cell therapy to be feasible in various patient populations, including children and elderly patients. In this issue of TRANSFUSION, four articles address the current state of NK-cell therapy, including novel applications and potential challenges. Koepsell and coworkers provide a detailed overview of clinical-grade NK-cell product manufacturing as well as a summary of published clinical trials, spanning a variety of therapeutic approaches. They underscore the importance of cell source, enrichment method, ex vivo activation, culture vessels, and cellular media in optimizing NK-cell manufacturing. As a minority of peripheral blood lymphocytes, NK cells are often purified, activated, and/or expanded before cellular therapy applications. One common approach is collecting cells by peripheral blood apheresis, and then selecting for NK cells using immunomagnetic beads. Alternatively, “feeder cells” can be added to NK cells in culture to promote proliferation. Types of feeder cells and culture conditions vary considerably across centers. In addition to engineering feeder cells to express costimulatory molecules, cytokines such as interleukin (IL)-2 and IL-15 can be added during the manufacturing process—each with differential effects on activation, proliferation, and survival. While these methods may increase cytotoxic activity in vitro, the subsequent effects on viability and cytotoxicity in vivo are unclear, as apoptosis is known to occur after IL-2 withdrawal in T cells. The primary objective of published studies has been feasibility and safety, and NK-cell infusions have proven to be exceptionally well tolerated. While responses are limited, some successes have been described. One potential barrier is that cellular therapies may be best deployed in the setting of minimal residual disease, and most studies have been in patients with active, high-risk malignancies. TRANSFUSION 2013;53:245-248.