The therapeutic potential of ex vivo expanded natural killer (NK) cells for immunotherapy of cancer
Author: Guven, Hayrettin
Date: 2005-12-09
Location: Föreläsningssalen 4U Solen, Alfred Nobels allé 8
Time: 9.00
Department: Institutionen för medicin, Huddinge Sjukhus / Department of Medicine at Huddinge University Hospital
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Thesis (4.756Mb)
Abstract
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.
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.
List of papers:
I. Carlens S, Gilljam M, Chambers BJ, Aschan J, Guven H, Ljunggren HG, Christensson B, Dilber MS (2001). A new method for in vitro expansion of cytotoxic human CD3-CD56+ natural killer cells. Hum Immunol. 62(10): 1092-8.
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II. Guven H, Gilljam M, Chambers BJ, Ljunggren HG, Christensson B, Kimby E, Dilber MS (2003). Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy. Leukemia. 17(10): 1973-80.
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III. Guven H, Konstantinidis KV, Alici E, Aints A, Abedi-Valugerdi M, Christensson B, Ljunggren HG, Dilber MS (2005). Efficient gene transfer into primary human natural killer cells by retroviral transduction. Exp Hematol. 33(11): 1320-1328.
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IV. Guimaraes F, Guven H, Donati D, Christensson B, Ljunggren HG, Bejarano MT, Dilber MS (2005). Evaluation of ex vivo expanded human NK cells on anti-leukemia activity in SCID-beige mice. [Submitted]
V. Barkholt L, Guven H, Treschow A, Conrad R, Cederlund K, Ljunggren HG, Aschan J, Christensson B, Gilljam M, Stellan B, Ringden O, Dilber MS (2005). Donor derived natural killer (NK) and natural killer-like T (NKT) cell infusions are safe with a potential biological anti-tumour effect. [Manuscript]
I. Carlens S, Gilljam M, Chambers BJ, Aschan J, Guven H, Ljunggren HG, Christensson B, Dilber MS (2001). A new method for in vitro expansion of cytotoxic human CD3-CD56+ natural killer cells. Hum Immunol. 62(10): 1092-8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Guven H, Gilljam M, Chambers BJ, Ljunggren HG, Christensson B, Kimby E, Dilber MS (2003). Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy. Leukemia. 17(10): 1973-80.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Guven H, Konstantinidis KV, Alici E, Aints A, Abedi-Valugerdi M, Christensson B, Ljunggren HG, Dilber MS (2005). Efficient gene transfer into primary human natural killer cells by retroviral transduction. Exp Hematol. 33(11): 1320-1328.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Guimaraes F, Guven H, Donati D, Christensson B, Ljunggren HG, Bejarano MT, Dilber MS (2005). Evaluation of ex vivo expanded human NK cells on anti-leukemia activity in SCID-beige mice. [Submitted]
V. Barkholt L, Guven H, Treschow A, Conrad R, Cederlund K, Ljunggren HG, Aschan J, Christensson B, Gilljam M, Stellan B, Ringden O, Dilber MS (2005). Donor derived natural killer (NK) and natural killer-like T (NKT) cell infusions are safe with a potential biological anti-tumour effect. [Manuscript]
Issue date: 2005-11-18
Rights:
Publication year: 2005
ISBN: 91-7140-564-X
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