Developing IL-15 superagonists for cancer therapy

Admin on 01 / 10 / 2020 under #CancerTherapy

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 (T_regs). The first two negate the adverse effects highlighted above and the latter is important because binding to T_regs 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.