Richard
Sachse discusses how immunotherapies targeting interleukin 15 (IL-15)
signalling can be optimised to enhance their efficacy and limit off-target
effects.
In
this article, Drug Target Review’s Hannah Balfour discusses
with Chief Medical Officer of SOTIO, Richard Sachse, why interleukin 15 (IL-15)
signalling has become a top target for cancer immunotherapies and how they
designed their drug (SO-C101) to overcome some of the limitations of previous
IL-15 and IL-2 targeted therapies.
Why
target IL-15? What are the advantages of this over cancer treatments that are
already under development or in the clinic?
Studies
have shown that expression of the IL-15 cytokine within human tumours is
crucial for optimal antitumour immune responses. It has become a highly
attractive oncology target because IL-15 signalling activates two of the most
important cell types for driving an antitumour response: cytotoxic (CD8+) T
cells and natural killer (NK) cells.
Stimulating
the IL-15 receptor on these cells causes a potent immune response that could be
complimentary to a variety of currently existing therapies, including PD-1 inhibitors.
Other
similar treatments have previously targeted IL-2 signalling and have acted as a
proof-of-concept for our IL-15 targeting therapies. The IL-2 and IL-15
receptors share common subunits and functions. IL-2 also activates cytotoxic T
cells and NK cells. However, despite success in clinics when treating renal
cell carcinoma and melanoma, IL-2 therapies are associated with adverse events,
such as vascular leakage. These off-target effects are caused by the therapies
binding to IL-2 receptors expressed in the lung epithelia and vascular
endothelium. IL-15 receptors are not expressed in these locations and so IL-15
have distinct advantages over IL-2 immunotherapies.
How
does SO-C101 target IL-15 signalling to produce a therapeutic effect?
SO-C101
is a subcutaneously administered IL-15 superagonist that demonstrates high
specificity for the IL-2 and IL-15 receptors on cytotoxic T cells and NK cells.
A superagonist is an analogue of a natural ligand for a receptor (in this case,
IL-15) that is able to produce a maximal response – greater than the natural
ligand can produce – so has an efficacy of 100 percent.
IL-2
and IL-15 receptors share the same beta and gamma subunits, which are expressed
on NK and cytotoxic T cells. However, the IL-15 receptor alpha chains are
expressed on dendritic cells. For IL-15 to bind to its receptor and create a
response, all these cell types (NK, cytotoxic T and dendritic cells) must be in
close proximity. In creating our IL-15 superagonist, we have bypassed the need
for dendritic cells to express the alpha subunit by designing the drug as
a human fusion protein of IL-15 and the IL-15 receptor
alpha chain.
The
SO-C101 product is designed to have an optimised half-life that allows the drug
to stimulate T cells and NK cells physiologically, through pulses in cytokine
concentration. IL-15 agonists with extended half-lives can cause T cells and NK
cells to become exhausted due to tonic (constant) stimulation. The shorter
half-life of SO-C101 avoids this, enhancing the efficacy of the drug by
enabling pulsatory stimulation.
The
drug also does not bind to IL-2 receptors on lung epithelia, vascular
endothelium or regulatory T cells (Tregs). The first two negate the
adverse effects highlighted above and the latter is important because binding
to Tregs could potentially activate them, weakening the immune
response and lowering the therapeutic efficacy of the drug.
How is the
drug performing in pre-clinical trials?
Our
pre-clinical results for SO-C101 alone are very promising; in in
vivo tumour models the drug showed increased long-term survival and
tumour regression. When it was combined with other immunotherapies, such as
checkpoint inhibitors and antibody-dependent cell cytotoxicity (ADCC)
monoclonal antibody (mAb) therapies, there were clear signals of a synergistic
mode of action between SO-C101 and the other cancer therapies in vivo.
We see clear signs of biological activity in the ongoing Phase I trial.
What
are you excited about in the field of cancer immunotherapies?
Aside
from exploring the capabilities of IL-2 and IL-15 superagonists and their
potential for use in combinatorial therapeutic strategies, I am really excited
about the further development of cellular treatment options, such as chimeric
antigen receptor (CAR) T-cell therapies for solid tumours. So far, cellular
therapies have been proving beneficial effects in liquid tumours but have had
limited efficacy in solid ones. I am looking forward to the potential
breakthrough treatment option that next-generation CAR T therapies could
provide for patients.
I
started my career as a physician practising internal medicine and it has been
fascinating to see the advancement of therapeutic options for patients with
oncologic diseases for which, at the time when I was practising, there was no
treatment available so outcomes were poor. The progress we have made is
incredible – when I was at medical school, for certain diseases, there was no
such thing as a five-year survival rate and now we talk about 10-year survival
rates for the same conditions.
What
does the future hold for SO-C101?
In
our monotherapy dose escalation trial for SO-C101 we have observed positive
effects on NK and T-cell activation and expansion in patients with advanced or
metastatic solid tumours. The drug is also in a trial evaluating its effects on
the same tumours in combination with a PD-1 checkpoint inhibitor
(pembrolizumab), but this is only in its early stages.
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