During the past decade, natural killer (NK) cells have emerged as attractive candidates for cellular therapy against cancer. The current project aim at developing a completely new and superior way to expand cytotoxic lymphocytes with a given specificity, enabling a predictable and more potent tumor cell killing. The invented platform technology can be implemented in research as well as in clinical-grade expansion of highly cytotoxic NK cells as a novel therapeutics for many cancer types including refracto ry AML, acute lymphoid leukemia (ALL) and malignant lymphoma. Other putative therapeutic targets include tumor types with evidence of frequent loss of HLA class I molecules including malignant melanoma and neuroblastoma. The strategy fills a gap for patients who are refractory to conventional chemotherapy or in those with indication for allogeneic stem cell transplantation but lacking stem cell donor or at threatening relapse following cord blood transplantation when no donor lymphocytes are available for donor lymphocyte infusion (DLI). In the long-term perspective, the technology may also provide a replacement for allogeneic stem cell transplantation, which is a cost-intensive and high-risk procedure.
Natural killer (NK) cells have the ability to recognize tumors without prior sensitization. Yet, it is not until recent years that we have gained insights into their fine specificity and begun to unravel their potential in clinical therapy for patients wi th cancer (Ljunggren and Malmberg, Nature Reviews Immunology 2007). In the present project, we aim to optimize and validate a platform for the next generation of NK cell therapies based on new insights into the functional maturation of NK cells. Our recen t findings suggest that it is possible to selectively expand NK cells of a given specificity, guided by the HLA of the recipient, for cancer therapy. The strategy can be personalized to fit the HLA class I type of the recipient, thereby promoting NK cell- mediated alloreactivity. A key aspect of the invention is the discovery that NK cell education by killer cell immunoglobilin-like receptors (KIRs) binding to self-HLA class I molecules (self-specific KIRs) is essential for the proliferative responses of N K cells. This insight make it possible to, for example, expand KIR2DL1 single-positive NK cells from HLA-C2 homozygous donors, displaying strong alloreactivity against cancer cells from HLA-C1 homozygous patients. Although there are many alternative strat egies for ex vivo expansion of NK cells that are currently being implemented in the clinic, none of these yields a predictable and specific expansion of single KIR+ NK cells. Another conceptual novelty of the proposed platform is the specific generation of highly differentiated, memory-like NKG2C+ NK cells that lack expression of the inhibitory receptor NKG2A. All other concurrent platforms for ex vivo NK cell expansion lead to the preferential expansion of NKG2A+ NK cells which dampen their activity aga inst tumor cells, many of which express high levels of HLA-E.