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144 | Chapter 6 Allogeneic NK cells from human umbilical cord blood cells NK cells represent a promising immunotherapeutic treatment option for cancer. Stem cell progenitors from cord blood offer a unique clinically applicable platform for the expansion and differentiation of cytotoxic NK cells. The low immunogenicity of cord blood cells strongly reduces the risk of relapse and GvHD after transplantation 1 . Considering the advantages of using cord blood, Glycostem Therapeutics, a clinical stage biotech company, which in the last decade has developed a flexible platform technology to expand and differentiate NK cells from CD34+ cells 2 , upgraded this into a large scale GMP UCB-NK platform for clinical implementation (oNKord ® ) 3 . UCB-NK cells were infused at up to 30 x 10 6 cells/kg/bodyweight in elderly AML patients, resulting in excellent safety and early signs of efficacy in a phase I trial. Infused oNKord ® cells showed active migration to the marrow and further matured in the absence of any exogenous cytokine injections. This confirms previous findings from a preclinical model, showing migration to the bone marrow and upregulation of KIRs and CD16a in vivo as well as antileukemic activity 4 . oNKord ® is well characterized and was found to have a similar functionality and gene expression profile as PBNK cells 5 . Furthermore, as demonstrated in this thesis, oNKord ® is highly cytotoxic against solid tumor targets such as cervical cancer cells, in which killing was independent of HLA expression levels, tumor histology and HPV types 6 , or colorectal cancer cells, in which killing was independent of tumor EGFR levels, and RAS and RAF mutations 7 , thus paving the way for oNKord ® as immunotherapy for advanced solid tumors. It has become clear from the in vitro and in vivo experiments described in this thesis, using cervical, colon and epidermoid carcinoma cells, that activated allogeneic NK cells can be used to efficiently target different solid tumor types, with superior toxicity exhibited by UCB-NK cells. However, not all tumor targets are sensitive to NK cell killing and these underlying differences need to be addressed to improve the clinical efficacy of NK cell-based cancer immunotherapy. Several strategies are being explored that aim to improve the anti-tumor potency of NK cells, which may also be applied to the UCB-NK platform. A summary of currently applied and newly developed NK cell potentiating lead products of biotech companies and potential gene modification approaches are discussed below. Approaches to augment NK cell functions as pursued by biotech industries As reviewed in chapter 1, various clinical trials have been published, mainly initiated by academia, proposing allogeneic NK cells as an effective therapeutic option. As a result of these studies, interest in NK cell-based immunotherapy strategies has been engendered in an increasing number of biotech companies. Clinical trials conducted in academia are often restricted to phase I or II, as progression of experimental therapies to Phase III clinical trials and further on to commercialization and marketing requires a level of funding that surpasses the capacity of academic institutions. The financing of market enabling studies