Science

Treating cancer by modulating IL-21 activity

Activation of the cytotoxic function of natural killer (NK) and CD8+ T cells is critical to mount an effective anti-tumour immune response, and this mechanism is the basis for successful immunotherapeutic agents.

It is well established that interleukin-21 (IL-21) stimulates effector cells in the tumour microenvironment and could be a useful therapeutic agent alone or in combination with other established immunotherapeutic treatments1-3.

Bioinformatics analyses consistently reveal that higher expression of IL-21 and its specific receptor subunit, IL-21 receptor alpha chain (IL-21R), are associated with improved prognosis in a range of oncology indications, and with anti-tumour immune activation signatures.

There have been several Phase 1 and 2 clinical trials assessing recombinant human IL-21 (rhIL-21) in oncology as monotherapy, in combination with therapeutic antibodies (e.g. cetixumab (Erbitux)), in combination with small molecules targeting oncogenic kinases (e.g. sorafenib (Nexavar)), and in combination with a checkpoint inhibitor4. Reversible haematological and hepatic dose limiting toxicities were observed in approximately 15% of patients enrolled in these studies (N=291).

Despite these studies having been primarily designed to assess the safety and tolerability of rhIL-21, potential efficacy was suggested in a variety of Stage IV tumours (e.g. renal cell carcinoma, metastatic melanoma, colorectal cancer and Non-Hodgkin’s lymphoma) with an average overall response rate (ORR) of 16% (range 3.5-42%) warranting, in the opinion of lead investigators, further investigation of IL-21 as a therapeutic option for oncology5,6.

As inflammatory sites such as the tumour microenvironment (TME) or tumour draining lymph node (TDLN) have higher expression of IL-21 than non-inflammatory sites (e.g. the periphery), Pio Tx has licensed from Monash University the agonist antibody PIO-001, which has the capacity to induce, amplify, or sustain highly selective and localized anti-tumour activity. The research that led to the discovery and initial characterization of PIO-001 was conducted in the laboratories of Professor Charles Mackay, Professor Di Yu, and Dr Remy Robert.

Pio Tx is developing PIO-001 in order to capitalise on the therapeutic potential of IL-21 without the safety, dosing, and long-term immunological liabilities of systemic administration of a recombinant cytokine.

References:

1-Davis MR et al. (2015) Cancer Lett, 358(2):107-114 doi.org/10.1016/j.canlet.2014.12.047
2-Lewis et al. (2018) Oncoimmunology, 7(1): e1377873 DOI: 10.1080/2162402X.2017.1377873
3-Skak K et al. (2008) Immunology 123(4): 575–583 doi:10.1111/j.1365-2567.2007.02730.x
4-Young et al. (2016) Seminars in Oncology, 41: 623-636 doi.org/10.1053/j.seminoncol.2014.08.002
5-Grunwald et al., (2011) Acta Oncologica, 50(1):121-6 DOI: 10.3109/0284186X.2010.509104
6-Petrella et al. (2013) J. Clinical Oncology 31:15_suppl, 9032 DOI:abs/10.1200/jco.2013.31.15_suppl.9032