COMMENTARY

Improving natural killer cells

H Klingemann

Tufts-New England Medical Center, Boston, Massachusetts, USA

Donor lymphocyte infusions after stem cell transplantation

have taught the cancer community that human immune

cells have the potential power to control growth of and

even eliminate a malignant clone. Although infusion of

allogeneic T lymphocytes after stem cell transplantation

has become part of the treatment algorithm, either to

prevent or treat recurrent disease, it carries the risk of

acute graft-versus-host disease (GvHD) and does not work

well against diseases with high proliferative activity. T

lymphocytes can be made more targeted, as we have learnt

from the studies with expanded T cells against viral

antigens (Ag) [1] and through transfection with chimeric

Ag receptors (CAR) recognizing tumor cell Ag [2].

Recently the ‘little brother’ (or sister) of the lymphocyte

population, the natural killer (NK) cell, has experienced

renewed attention as an immunologically active cell. Major

histocompatibility complex (MHC) restriction in the

classical sense is not required for NK cells to become

activated. In fact they ‘see’ only MHC disparate targets,

which will block their inhibitory receptors. The Perugia

group was the first to observe that relapse in patients after

MHC haplo-mismatched transplant for acute myeloid

leukemia (AML) was reduced when killer cell inhibitory

receptors (KIR) of donor NK cells were blocked [3].

Analyzes from large studies suggested that such an effect is

only seen when T cells are depleted from the graft and the

weaker NK-mediated graft-versus-leukemia (GvL) effect

has the opportunity to surface. In patients not receiving a

transplant, Miller et al. [4] demonstrated that infusion of

allogeneic KIR-mismatched NK cells could induce a

remission in 5/19 patients with advanced leukemia, further

supporting the notion that allogeneic NK cells can display

anti-leukemic activity.

In addition to their expansion potential, it is also

desirable to produce tumor-specific NK cells by genetic

engineering. Unfortunately the transfection efficiency of

peripheral blood NK cells is very low, although some

recent reports using lentiviruses seem to result in better

transfection efficiency [5]. Allogeneic clonal cell lines, on

the other hand, are much easier to transfect and even allow

transfection with ‘safe’ non-viral based vectors and mRNA

[6].

The study by Jiang et al. [7] in this issue used the clonal

NK cell line NKL to show that transfection with the

interleukin (IL)-15 gene broadens and increases the

cytotoxic activity of the cells, and augments expression

of genes for perforin and granzyme. The study also

confirms the high transfection efficiency of cell lines

with simple electroporation, which has been shown for

NK-92 [8]. Cytotoxic NK cell lines can be expanded

under good manufacturing practice (GMP) conditions and

infusion into patients appears to be safe, but with clear

efficacy data still pending [9]. The study by Jiang et al. [7]

further supports the notion that allogeneic NK cell lines

represent a promising platform for engineering and

‘customizing’ NK cells to broaden their cytotoxic spectrum

and increase their cytolytic activity.

References

1 Gottschalk S, Bollard CM, Straathof KC et al. T-cell therapies.

Ernst Schering Found Symp Proc 2006;4:69�82.2 Brentjens RJ, Santos E, Nikhamin Y et al .Genetically targeted T

cells eradicate systemic acute lymphoblastic leukemia xenografts.

Clin Cancer Res 2007;13:5426�35.3 Ruggeri L, Capanni M, Urbani E et al. Effectiveness of donor

natural killer cell alloreactivity in mismatched hematopoietic

transplants. Science 2002;295:2097�100.4 Miller JS, Soignier Y, Panoskaltsis-Mortari A et al. Successful

adoptive transfer and in vivo expansion of human haploidentical

NK cells in patients with cancer. Blood 2005;105:3051�7.

Correspondence to: Hans Klingemann, MD, PhD, Tufts-New England Medical Center, 750 Washington Street, Mail 245, Boston, MA 02111, USA.

E-mail: hklingemann@tufts-nemc.org.

Cytotherapy (2008) Vol. 10, No. 3, 225�226

– 2008 ISCT DOI: 10.1080/14653240802028376

5 Su S, Nguyen DM, Smith A et al. Effective gene transfer into

human NK cells using an HIV-1-based lentiviral vector system.

ASH abstract. Chilr, R. Personal communication.

6 Rabinovich PM, Marina E, Komarovskaya et al. Synthetic

messenger RNA as a tool for cell therapy. Human Gene Therapy

2006;17:1027�35.7 Jiang W, Zhang ZJ, Tian Z. Functional characterization of the

interleukin-15 gene transduction into human natural killer cell

line (NKL). Cytotherapy 2008;10:256�74.

8 Mueller T, Uherek C, Maki G et al. Expression of a CD20-specific

antigen receptor enhances activity of NK cells and overcomes

NK-resistance of lymphoma and leukemia cells. Cancer Immunol

Immunother, DOI 10.1007/s00262-007-0383-3.

9 Arai S, Kindy K, Swearingen M et al. Phase I study of adoptive

immunotherapy using the cytotoxic natural killer (NK) cell line,

NK-92, for treatment of advanced renal cell carcinoma and

malignant melanoma. Blood 2003;102:693a.

226 H Klingemann