Cytokine Therapy

The main goal of modern cancer drug development is to provide patients with better, more targeted therapies. Conventional treatments such as chemotherapy and radiation don’t discriminate between cancer cells and healthy cells, leading to unwanted side effects. Unlike conventional treatments, immunotherapy exploits our immune system’s ability to recognise and kill only cancer cells while sparing healthy cells.

Cytokine therapy is a type of immunotherapy that directly activates the immune system to detect and kill cancer. In this article, we’re answering your questions about cytokine therapy to get you up to speed with the latest advances in this exciting field.

We’ll begin with an introduction to cytokines – what they are and how they work – before delving into how cytokines can be used as cancer immunotherapy. We’ll talk about the cytokine therapy drugs already approved for use in the clinic, some of the challenges being faced by these therapies and strategies that can be used to address these issues. Finally, we’ll tell you how we’re creating new cytokine therapies here at Audax Biosciences, and how next-generation cytokine therapies can revolutionise cancer treatment.

Cytokine basics: what are they and what do they do?

What are cytokines?

Cytokines are powerful proteins that carry signals between cells to control the way our immune system operates. So where do cytokines come from? Almost every cell in the body can make cytokines that affect the immune system. They can be made by cells and stay stuck to their surface, where they act locally only on nearby cells. Or they can be released into the body to act on other cells further away. Cytokines can even act on the same cell that makes them. In each of these ways, cytokines are the messages that tell immune cells when and where they need to act to fight disease.

What are the different types of cytokines?

There are many different types of cytokines, including interleukins, chemokines, interferons, colony-stimulating factors, and tumour necrosis factors. These names reflect what the cytokines do, for example, interleukins are messengers between immune cells called leukocytes (white blood cells).

What do cytokines do?

The short answer is that cytokines allow cells to communicate with each other. They control the response of our immune system to things that could harm us, including bacteria, viruses, injury or cancer. The long answer is…it’s complicated.

There are many different things that cytokines can do because there are many different types of cytokines. While some cytokines control the immune response to invading bacteria, viruses or parasites, other cytokines pump the brakes on the immune system once the danger has passed. Each cytokine can also do different things depending on which cells are involved, and in which part of the body. And to complicate things further, cytokines don’t just act on the immune system – they are involved in almost all biological processes, from the development of embryos to the way we age.

To convey messages between cells, cytokines are usually produced by one cell and then stick to their specific receptor on another cell, like a lock and key. The binding of a cytokine to its receptor then triggers changes in the cell – these might include growth, activation, suppression, making more cells (proliferation) or changing into a different cell type all together (differentiation). Cytokines therefore have the power to control immune cells, either activating or suppressing our immune response.

Let’s take a look now at some examples of cytokines and what they do.

Interleukin-12

Interleukin-12 (IL-12) is a potent cytokine with a range of effects on the immune system, including enhancing inflammation. For this reason, IL-12 is considered “pro-inflammatory”.

In the context of cancer, IL-12 is mainly produced by immune cells called macrophages and dendritic cells and has a range of effects on the tissue containing cancer cells, also known as the tumor microenvironment.

IL-12 activates immune cells called cytotoxic lymphocytes – in the cancer battlefield; these cells are the front-line soldiers of the immune system. As well as activating these soldiers, IL-12 helps to recruit more soldiers to the front line, gives them expert training by causing them to differentiate, and provides them with more powerful weapons in the form of interferon gamma (IFN-γ) production.

High levels of the cytokines IL-12 and IFN-y cause cancer cells to become more visible to the immune system so that they can be killed more easily. This makes IL-12 incredibly important in the immune system’s recognition of and response to cancer.

Transforming growth factor-beta

Transforming growth factor-beta (TGFβ) is another powerful cytokine that is involved in a wide range of biological processes. It acts as a tumour suppressor, helping to kill cancer cells in the early stages of their development.

However, like many cytokines, TGF-β can be a double-edged sword. In the later stages of cancer, it can actually promote cancer growth and cancer spread throughout the body (metastasis). Many different types of cancers are associated with abnormal TGF-β signalling, including lung, breast, prostate, and colon cancers.

What is cytokine therapy for cancer treatment?

Giving cytokines as cancer treatment – an approach termed cytokine therapy – has been extensively researched over the past 40 years. Let’s explore how cytokine therapy works, a few examples of cytokine therapies, some of the ongoing challenges in the cytokine therapy field, and some approaches to overcoming these obstacles.

What is cytokine therapy?

Cytokine therapy usually involves delivering synthetic cytokines throughout the whole body to treat disease. Cytokine therapy is most common in cancer and disorders of the immune system, including autoimmune disease.

The goal of using cytokines in cancer immunotherapy is to activate the immune system, particularly those soldiers we mentioned earlier whose job it is to kill cancer cells – the cytotoxic lymphocytes. Cytokine therapy exploits the ability of these cells to distinguish between healthy cells and cancer cells, preferentially killing the latter.

Cytokine therapy works differently from conventional immunotherapies, such as immune checkpoint blockade (ICB). While ICB prevents cytotoxic lymphocytes from being “switched off” when responding to cancer, cytokine therapy helps these cells “switch on” when they encounter cancer cells.

Are there any approved cytokine therapy drugs for cancer?

There are only two FDA-approved cytokine therapy drugs being used in cancer immunotherapy. One of these is proleukin, also known as aldesleukin. This drug is a synthetic form of IL-2 and was approved by the FDA for the treatment of both metastatic melanoma and metastatic renal cell carcinoma. The other is interferon alpha (IFN-α), which was approved for the treatment of blood cancers and melanoma.

What are the obstacles to the clinical use of cytokine therapies?

When there are so many cytokines with powerful effects on the immune system’s ability to fight cancer, why has it been so hard to get them into clinical use? Unfortunately, there are several barriers to using cytokines as cancer drugs:

• they can be toxic
• they are cleared very quickly from the body, requiring repeated high doses
• they are unable to target cancer cells directly, leading to unwanted effects on healthy cells, and
• they can sometimes have unintended effects and suppress the immune response to cancer.

All of these factors are currently preventing cytokine therapy from being regularly prescribed as a cancer treatment.

The biggest problem is that injecting cytokines into the body causes major side effects or toxicities, some of which can be fatal. This is made worse by the fact that cytokines are cleared very quickly from the body. Frequent administration of high doses is usually required for cytokine therapy to be effective.

As we mentioned earlier, cytokines have many different effects and act upon many different types of cells. This means that even if the intended outcome of cytokine therapy is achieved, there can be other unintended, and sometimes negative consequences.

One such example is IL-10 (pegilodecakin) , a cytokine therapy which was tested in cancer patients because it was very good at activating and increasing the numbers of cancer-killing immune cells. The problem was that IL-10 can also suppress different immune cells that are critical for cancer patients to fight infections. It is counterproductive to make patients vulnerable to other serious diseases during their cancer treatment.

What are the current approaches to next-generation cytokine therapy?

The holy grail of cytokine therapy is to design treatments that have good drug-like qualities, specifically target the tumour and have minimal side effects. Many research organisations have invested significant resources into this effort, aiming to overcome the challenges listed above that have historically limited the cytokine therapy field.

Unfortunately, several high-profile next-generation cytokine therapies designed to achieve this goal have failed early in clinical trials. These setbacks underscore the need for a deeper understanding of how to maximise clinical efficacy while minimising toxicity.

The main strategies being explored to accomplish this in next-generation cytokine therapy include:

• Modified cytokine variants: Changes are made in the lab to improve the effectiveness of cytokines, including altering how tightly they bind to their receptor, making them persist longer inside the body and allowing them to only act on a cell expressing a certain version of the receptor.
• Cytokine checkpoint inhibitors: These drugs enhance cytokine receptor signalling and duration in immune cells, so they can more efficiently respond to the cytokines produced within the tumour.
• Immuno-cytokines: Cytokines are attached to other proteins called antibodies, redirecting them towards a specific target.
• Small molecule agonists: Drugs that mimic the effects of cytokines and selectively activate cytokine receptors to kill cancer cells.
• Alternate delivery technologies: Cytokines (proteins or mRNA) are packaged within biological structures (e.g. liposomes) or attached to the surface of nanoparticles, allowing controlled release and/or localised delivery of cytokine therapy.

Are targeted, engineered molecules the future of cytokine therapy?

At Audax Biosciences, we’re rethinking immuno-oncology and developing bold new strategies to drive safe and effective cytokine therapies into the clinic. As a leading immunotherapy company, we’re actively reshaping the future of cytokine therapy with our Avikine®platform and lead therapeutic candidate, DAX-044.

What is the Avikine® Platform?

Avikine® molecules are the world’s most advanced immuno-cytokines, delivering the right cytokine signal to the right immune cell in the right tissue context. We have solved the typically poor drug-like characteristics of cytokines by reimagining the principle of avidity-based targeting.

By understanding when and where cytokines can be used to treat disease, we can engineer specific targeting and drug-like properties into these biologic molecules. The result is carefully designed molecules – with optimised functional domains that can restore cytokine signals where required and avoid off-target tissues.

This platform has applications in immuno-oncology and other immune-related diseases.

DAX-044: A targeted IL-12 cytokine therapy

DAX-044 is an Avikine® molecule and our lead therapeutic candidate – a new therapy that aims to harness the potent anti-cancer effects of IL-12 to treat a variety of solid cancers, particularly hard-to-treat cancer types that historically have not responded well to conventional immunotherapies.

DAX-044 comprises an IL-12 domain that has modified receptor binding characteristics to avoid the toxic side effects that have been seen with delivering standard IL-12 throughout the body. This is then fused to two other protein domains that extend it’s half-life in the circulation and target it to specific cells within the tumour. These multiple functional domains combine to essentially create a biological ‘logic-gate’ – a molecule that is active in the tumour and inactive in tissues that cause toxicity.

How can next-generation cytokine therapies be moved into the clinic?

One of the most interesting questions we move forward in the cytokine therapy field is how broadly these therapies can be used in patients, since conventional immunotherapies such as ICB are restricted to specific cancer types. It will be fascinating to see whether cytokine therapy can be used to treat cancers that have not responded well to other treatments like ICB, as well as other cancer types that cannot be treated with ICB in the first place.

With more development and research, cytokine therapies may emerge as stand-alone treatments, used in combination with ICB, or could even be used to improve the effectiveness of cellular immunotherapies, broadening the range of cancers they can treat. At Audax Biosciences, we're aiming to bring multiple Avikine® candidates to the clinic in the near future, beginning with DAX-044, so that we can start transforming the lives of patients.

We hope this article helped you to understand the basics of cytokine therapy and why we’re so passionate about it here at Audax Biosciences. We believe we’re only just beginning to scratch the surface of the true potential of cytokine therapy. If you want to learn more about immuno-oncology and cytokine therapy, watch this space – we’ll be posting more articles soon! You can also follow us on LinkedIn