The therapeutic potential of ex vivo expanded natural killer (NK) cells for immunotherapy of cancer

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine at Huddinge University Hospital

Sammanfattning: Cell and gene therapy of cancers has received much attention in the past decade. A number of applications of cancer treatment have been developed and used. One of the recent applications is immunotherapy of tumours with human natural killer (NK) cells. A major challenge to the successful application of this treatment has been the identification, expansion, and gene modification of appropriate effector cells. We therefore developed a novel expansion method that is simple, good manufacturing practice (GMP)-compatible, cost-effective (Paper I). For NK cell immunotherapy of patients with B-cell chronic lymphocytic leukaemia (B-CLL), efficient NK cell expansion was obtained using the same method (Paper II). However, NK cell expansion rates were lower in cultures from patients with progressive B-CLL, demonstrating the negative effect of disease progression on NK cell expansion. In the same study (Paper II), it was also demonstrated that samples obtained from the same patients at different time points had similar NK expansion capacity, indicating reproducibility and also the reability of the method. In addition, in both studies it was shown that half of the expanded T cells possess an NK-like T (NKT) phenotype (CD3+CD56+). Moreover, using retroviral vector transduction, efficient gene transfer into primary human ex vivo expanded NK cells was demonstrated. Days 5 and 6 of expansion seem to be the best days for NK cell transduction (Paper III). In addition, the safety and the in vivo anti-tumour activity of human ex vivo expanded NK cells were evaluated against human K562 cells in SCID-beige mice (Paper IV). Mice treated with expanded NK cells had significantly prolonged survival compared to the untreated group. Finally, NK and NKT cell populations that were expanded with GMP components were infused into patients with tumors. Such killer cells with or without IL-2 injections were shown to be safe and to some extent had anti-tumor activity (Paper V). In conclusion, these studies have shown that NK as well as NKT cell expansion is possible with such a simple, cost effective and easy-to-use method. We were able to expand and gene-modify with retroviral vectors NK cells directly from the peripheral blood of both healthy donors and patients with B-CLL and show that NK cells can eradicate tumour cells in vivo. This may open new possibilities for current and future cell- and gene therapy approaches.

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