In this article, Dr Bruce Dezube
explains why new cancer immunotherapy drugs that utilise the IL-2 pathway with
lower side effects could offer more benefits compared to high-dose IL-2
treatment.
As an oncologist for the past 34
years, I have seen how the cancer treatment landscape has evolved. In the early
days, these treatments primarily included three modalities: chemotherapy, with
only a handful of options; radiation therapy; or surgery. There were no
targeted therapies available. However, over the years, we have seen incremental
improvements in treatment options – until more recently when immunotherapies,
such as checkpoint inhibitors, took centre stage and revolutionised the way
that cancer is treated.
The advent of these immunotherapy
approaches significantly improved clinical outcomes in many cancer types.
However, immune checkpoint inhibitors are not an option for all cancer types:
pancreatic and ovarian cancer, as well as most haematologic malignancies, do
not have approved immuno-oncology (IO) options. Furthermore, many patients with
cancer do not benefit from immunotherapies; for example, the response rates for
single-agent immune checkpoint inhibitors in ovarian cancer is only ~six to 15
percent.1 Even patients with cancer types eligible for IO who
respond initially may develop resistance after treatment. Suboptimal
CD8+ T-cell response and activity of immune suppressive regulatory T cells are
believed to be the key drivers of this resistance.
Therefore, optimising the ability
of cancer-fighting T cells and countering the effects of Tregs continue
to be an active area of research today as companies attempt to develop the next
generation of IO treatments. In doing this, numerous companies are revisiting
previously existing therapies, such as interleukin-2 (IL-2), to develop
potential new IOs.
History of IL-2 as a cancer
therapy
In 1976, a T-cell growth factor –
which later became known as IL-2 – was identified. Soon afterward,
IL-2 was extensively studied in research laboratories. The first trial of
purified IL-2 in patients with solid tumours (melanoma, sarcoma, adenocarcinoma
and Kapsosi’s sarcoma) began in 1983, but while a few side effects were
observed, no antitumour activity occurred.
An important development was the
production of recombinant IL-2, which allowed easier access to larger
quantities of IL-2 and was first used in an oncology clinical trial in
1985. The half-life of IL-2 was determined to be seven minutes, so
administration every eight hours was needed to keep therapeutic IL-2 in the
patients’ bodies. Although tumour regression was observed in
patients with metastatic melanoma and metastatic renal cancer, significant
toxicities, including capillary leak syndrome, were associated with IL-2
therapy. High-dose IL-2 (aldesleukin) was eventually approved as the first
immunotherapy to treat metastatic renal cell carcinoma (RCC) in 1992, followed
by approval in melanoma in 1998.
Challenges of IL-2 in clinical
use
…optimising
the ability of cancer-fighting T cells and countering the effects of Tregs continue
to be an active area of research today”
A key challenge of using IL-2 in
the clinic lies in its two receptors: the intermediate affinity and high
affinity receptors.8 Binding to the intermediate affinity
receptor, expressed primarily on CD8+ T cells and NK cells, drives antitumour
activity; thus, for IL-2 therapies to be effective, they must activate this
receptor. However, IL-2’s binding to its high affinity receptor, expressed on Tregs,
suppresses immune responses including antitumour, by expanding these cells.
Since the high affinity receptor binds IL-2 more potently than the intermediate
affinity receptor, a low dose of IL-2 binds primarily to the high affinity
receptor on Tregs without effectively activating CD8+ T cells
and NK cells. A high dose of IL-2 is therefore needed to effectively activate
these cancer-fighting cells expressing the intermediate affinity receptor;
however, a high dose of IL-2 has also been reported to preferentially expand Tregs. Besides
immune suppression via Tregs, IL-2 therapy has been associated with
toxicities including capillary leak syndrome, which is believed to be driven by
vascular endothelial cells that express the high affinity receptor.15
Therefore, preferential
activation of the intermediate affinity receptor at a low dose has been the
challenge that pharma companies are aiming to address with new, investigational
IL-2 products.
The
IL-2 renaissance: why companies are revisiting this pathway
Drug discovery is a long, arduous
and cost-intensive journey, so shortening that timeframe and increasing the
likelihood of finding a new treatment is incredibly important for cancer
patients who are out of other options. The IO revolution has shown that
improving the ability of T cells to fight cancer is a viable option.
Accordingly, this provides strong rationale for revisiting the validated IL-2
pathway to see whether its cancer fighting arm can be selectively engaged by
designing molecules that specifically target the intermediate-affinity
receptor.
Modified
IL-2 as a potential solution
Since Tregs are
key players in treatment resistance and tumour escape, shifting the balance of
T cells to reduce the activity and ratio of Tregs within the
patient’s body has important implications for cancer treatment.10,11 Modified
IL-2s are designed to preferentially bind the immunostimulatory,
intermediate-affinity IL-2 receptor on antitumour CD8+ T cells and NK cells
instead of the immunosuppressive, high affinity IL-2 receptor on Tregs.
Pegylated IL-2
Developed in 1987, the first
pegylated IL-2 was designed to have the same binding properties as IL-2 but a
longer half-life. In a clinical trial published in 1995, it was shown that the
efficacy and safety profile of pegylated IL-2 was the same as non-pegylated
IL-2. More recently, a newer pegylated version of IL-2 was designed; the PEG
chains attached to the IL-2 protein block the binding of IL-2 to the
immunosuppressive high affinity receptor, allowing the pegylated IL-2 to be
directed only to the intermediate affinity receptor.
Tumour-directed
IL-2
Another approach for redesigning
IL-2 involves fusing IL-2 to an antibody that targets a common tumour antigen,
such as carcinoembryonic antigen or fibroblast activating protein. The IL-2
used in this approach must be mutated to prevent binding to the high affinity
receptor.
IL-2/IL-2Ra
fusion
An additional strategy for
modifying IL-2 rather uses circular permutation, a naturally occurring protein
rearrangement process, to fuse IL-2 with the alpha chain of the high affinity
IL-2 receptor. When the alpha chain is fused to IL-2, the resulting investigational
drug can no longer bind the high affinity IL-2 receptor on Tregs and
may only bind to the intermediate affinity receptor on antitumour CD8+ T cells
and NK cells.
At Alkermes, we have harnessed
circular permutation to pursue the development of a novel cytokine,
re-engineered from IL-2, that is designed to selectively expand tumour-killing
immune cells while avoiding activation of immunosuppressive cells.
This fusion protein design may
offer several advantages. It is an inherently active drug candidate that may
not need metabolic breakdown to be activated within the body. It is a highly
stable molecule, mitigating concerns about it breaking down into the native
form of IL-2, which could bind the high affinity receptors. Furthermore, this
novel design is intended to allow for both intravenous and subcutaneous
administration, potentially providing optionality for patients. The
selectivity, efficacy and safety of this fusion protein are currently being
investigated in clinical trials.
The IL-2 pathway has already
proven to be a validated therapeutic target in oncology. The development of
potential new drugs that leverage the proven clinical benefits of targeting
this pathway, with lower side effects, could offer a significant improved
benefit to risk profile compared to high-dose IL-2 treatment. In addition,
early clinical and pre-clinical data suggest that newer IL-2 variant
immunotherapies may be an appropriate addition to multiple other treatment
approaches, enhancing their potential role in patient treatment.
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