Adding Cytokine-Induced Killer Cells to a Virus Makes for a Cancer-Killing Combo

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Right place, right time

from Nature Reviews Immunology

Lucy Bird

The delivery of biological therapy to the right place at the right

time is a key aim for the treatment of cancer. Such directed

therapies will have an enormous advantage over non-specific

chemotherapeutic approaches that do not differentiate between cancer

cells and non-cancer cells. Reporting in Science, Thorne et al. have

found a way of combining two candidate antitumour approaches to

achieve specific targeting of tumours and to increase efficacy in

mouse tumour models compared with either approach alone.

The authors isolated a population of cells — which they named

cytokine-induced killer (CIK) cells — that are derived from human

peripheral blood or mouse splenocytes after culturing in the presence

of interferon-, interleukin-2 and CD3-specific antibody. The CIK

cells express T-cell markers and the natural killer (NK)-cell

receptor NKG2D (NK group 2, member D), through which they recognize

and kill cells expressing the stress-associated ligands MHC-class-I-

polypeptide-related sequence A (MICA) and MICB. Because MICA and MICB

are expressed under conditions of cellular stress, such as in the

tumour microenvironment and after viral infection, CIK cells can be

used to specifically target tumour cells in vivo despite not knowing

any tumour-specific antigens.

To further increase the cytolytic capabilities of CIK cells, the

authors infected them with a modified vaccinia virus. The key

advantage of this modified vaccinia virus is that it has been

engineered to preferentially replicate in and lyse transformed cells.

This was achieved by deletion of the viral genes encoding thymidine

kinase and viral growth factor. This modified virus, referred to as

double-deleted vaccinia virus (vvDD), only replicated in dividing

cells in which cellular thymidine kinase expression is upregulated

and in cells with dysregulated growth-factor-receptor signalling

(both common features of tumour cells).

Putting these two approaches together therefore provides a means to

target tumour cells and deliver a cytolytic agent in a synergistic

manner. The synergy is due, in part, to the replication of vaccinia

virus in CIK cells being delayed for more than 48 hours after

infection, allowing the CIK cells time to reach the tumour site

before releasing the lytic virus.

The authors used non-invasive bioluminescence imaging to track vvDD-

infected CIK cells following transfer to mice bearing tumours.

Importantly, two days after intravenous transfer, vvDD-infected CIK

cells were detected at the tumour site and were barely detectable in

other parts of the body. Moreover, vvDD-infected CIK cells were shown

to penetrate deeper into the tumour mass than vvDD delivered alone.

Next, the authors tested the antitumour efficacy of the combination

therapy compared with each therapy alone. Injection of

immunodeficient mice bearing established human peritoneal tumour

xenografts with CIK cells alone could extend the survival of the mice

by 8 days. Injection of vvDD alone increased survival by 15–16 days.

By contrast, the combination therapy resulted in a complete response

in all mice with no relapse for the duration of the study (90 days).

This efficacy of the combination therapy was also seen in

immunocompetent mice bearing mouse breast cancers. In this case,

injection of vvDD-infected mouse CIK cells resulted in complete

responses in six of eight mice, whereas injection of mouse CIK cells

and vvDD separately (but on the same day) resulted in a complete

response in only one of eight mice.

Although the animal models are encouraging, further studies will be

required to determine whether this combination approach will

translate to humans.

References

ORIGINAL RESEARCH PAPER

Thorne, S. H., Negrin, R. S. & Contag, C. H. Synergistic antitumor

effects of immune cell-viral biotherapy. Science 311, 1780–1784 (2006)

© 2005 Nature Publishing Group