04.2020 | THE SCIENTIST 53Rezvani and her colleagues’ own research,
meanwhile, has led to a partnership with
the Japanese pharmaceutical company
Takeda to take their NK cell work into
multicenter clinical trials.
Natural killers
NK cells were first described in the 1970s,
when Swedish and British researchers
independently discovered a new class of
immune cells that didn’t match the fea-
tures of T cells or B cells, but still laid
waste to cancerous cells. Ever since that
discovery, scientists have tried to harness
the cells’ powers to fight cancer. But it took
the more recent development of immune
checkpoint inhibitors, which showed that
it was possible to unleash and enhance
the immune response against cancer,
to throw open the door for cell-based
immunotherapies.
As it happened, CAR T cell therapy was
the first such therapy out of the gate—albeit
with a few obstacles. Most notably, T cell
treatment currently has to be autologous—
only a patient’s own T cells can be used. That’s
because of the way in which T cells interact
with the human leukocyte antigen (HLA)
complex, a group of cell surface proteins that
identifies a cell as being part of the self: any
change to the HLA complex on the surface of
a cell signals to a T cell that the cell is foreign.
While this sensitivity makes T cells effective
immune defenders, it has potentially deadly
consequences for T cell–based therapy, as
any mismatch between introduced and host
cells can lead to cytokine release syndrome or
graft-versus-host disease.
NK cells, by contrast, are much less
choosy about the HLA complex, says
Soyoung Oh, a cancer immunologist at
the biotechnology company Genentech.
Stressed cells, such as those that are
malignant or infected with a virus, may
have reduced expression of HLA proteins,
or, in some cases, none at all. They can
also produce stress-related proteins on
their surface. Either of these changes
triggers NK cells to release two types
of proteins that perforate a target cell’s
membrane, damage its vital organelles,
and induce cell suicide. This broad activ-
ity means that, unlike T cells, NK cells
don’t need any antigen-specific priming
to provide a therapeutic anticancer effect.
But typically, the mere presence of
any HLA complex on a cell surface can
be enough to signal NK cells to stand
down. Consequently, using another
person’s NK cells is less likely to trigger
the dangerous immune reaction that
an unfamiliar T cell might, says Oh,
allowing researchers to envisage mass-
producing NK cell therapies as an off-
the-shelf product that doesn’t need to be
immunologically matched to a patient.Unleashing the immune attack
Biotech companies are exploring various
sources of NK cells. Nkarta, for example,
harvests cells straight from the peripheral
blood of a donor using a technique called
leukapheresis, in which immune cells are
separated out from red blood cells. Other
companies are looking to umbilical cord
blood, which has a more concentrated
supply of NK cells and their progenitors
than peripheral blood.Still others are investigating the use
of stem cells, which can in principle be
differentiated into hematopoietic stem
cells (HSCs) that then generate NK cells.
Dan Kaufman, a hematologist at the
University of California, San Diego, has
been using both embryonic stem cells
and induced pluripotent stem cells—
stem cells derived from normal cells
such as skin cells—to generate NK cells.
(Kaufman is also collaborating with Cal-
ifornia-based Fate Therapeutics on its
NK cell immunotherapy program.)
Netherlands-based biotechnology
company Glycostem, meanwhile, manu-
factures its NK cells from hematopoietic
stem cells harvested from cord blood. In
2015, Glycostem released results from a
Phase 1 clinical trial in which 10 patientswith acute myeloid leukemia who had
relapsed after chemotherapy were
infused with varying doses of the compa-
ny’s unmodified cord blood–derived NK
cells. The study recorded no instances
of graft-versus-host disease or cytokine
release syndrome, and patients showed
significantly better survival compared
with historical controls. Tw o patients
even showed evidence of eradication of
minimal residual disease—a low but per-
sistent level of leukemic cells after treat-
ment that usually heralds relapse.
“For these patients,... they have
no therapeutic option actually, they
just have to wait for the relapse,” says
Didier Haguenauer, chief medical offi-
cer at Glycostem. After the success of
that single-dose study, the company
is now launching a clinical trial test-
ing a three-dose course of treatment.
“We expect repeat administration to
improve the efficacy of the treatment.”Boosting the killer instinct
Results from trials such as Glycostem’s
suggest that simply boosting a patient’s
population of unaltered NK cells could
be enough to help their immune system
overcome a cancer. But many research-
ers are also looking into mechanisms
that might enhance or better engage NK
cells’ anticancer actions.
As is the case for T cells, NK cells
are regulated and inhibited by immune
checkpoints. They are “a natural brake,
so that you potentially don’t lead to
autoimmune diseases or immuno-
pathologies from excessive activation,”
says Nicholas Huntington, who directs
the Cancer Immunotherapy Laboratory
at Monash University in Melbourne and
is the cofounder and CSO of oNKo-
Innate, an Australia-based biotech
developing NK cell therapies. Overrid-
ing those checkpoints, which Hunting-
ton helped identify for NK cells, could
be useful when it comes to targeting
cancer. “If we genetically delete these
checkpoints, then the natural killer cells
remain active and hyperfunctional, and
they can eradicate cancer much quicker,
can eliminate metastases much quickerSo fa r, NK cell therapies
haven’t shown any of the
significant toxicities that
plague CAR T cell therapies.