Identification of IL1RAP as a novel oncoprotein and therapeutic target in Ewing sarcoma

Ewing Sarcoma (EWS) is an aggressive form of childhood cancer that occurs on bone and soft tissue. Although conventional cancer therapeutic strategies, such as chemotherapy, radiation and surgery, have improved survival in patients with localized EWS tumours, they are ineffective for patients with metastatic disease. In addition, conventional chemotherapy is often toxic and carcinogenic, which carries short- and long-term toxicities. In the past few years, immunotherapy has been promoted as an effective means to prolong survival or eliminate tumor cells in patients with specific cancers.

However, effective immunotherapeutic strategies for EWS have not yet been described. Identification of highly specific cell surface markers of tumor cells is critical for developing targeted immunotherapy strategies. We have identified IL1RAP (Interleukin 1 receptor accessory protein) as a cell surface protein that is highly expressed in EWS in comparison to normal tissues/organs, and that is important for tumorigenesis in this disease. In this project, we aim to develop immunotherapeutic strategies by targeting IL1RAP in human EWS, while also delineating the key mechanisms mediating the tumor-promoting function of this protein.

End of Award Update – March 2022

Most exciting outputs

During the Health Research BC / Lotte & John Hecht Memorial Foundation award period, my work in Dr. Poul Sorensen’s lab identified IL1RAP (Interleukin 1 receptor accessory protein) as a cell surface protein that is highly expressed in Ewing sarcoma, but minimally expressed in pediatric and adult normal tissues, nominating it as a promising immunotherapy target. Our mechanistic studies show that IL1RAP maintains cyst(e)ine and glutathione pools in Ewing sarcoma, which are vital for redox homeostasis and metastasis.

To therapeutically target IL1RAP, we have collaborated with Dr. Dimiter Dimitrov of the University of Pittsburgh to develop IL1RAP binders via phage-display biopanning. We identified highly specific IL1RAP binders, one of which has been engineered into a humanized IgG1 antibody. This antibody can induce antibody-dependent cellular cytotoxicity (ADCC) in Ewing sarcoma cells. Moreover, in collaboration with Dr. Rimas Orentas of the Seattle Children’s Hospital, we have developed IL1RAP CAR (chimeric antigen receptor) T cells, which can mediate potent tumor cell killing in vitro, and we are currently optimizing the IL1RAP CAR for higher in vivo efficacy in mouse models. Some of these findings have been published in Cancer Discovery.

With regard to the mechanistic studies of the pathobiological function of IL1RAP, i.e. IL1RAP maintains cyst(e)ine and glutathione pools that promote Ewing sarcoma metastasis, we recently published a review article on this topic in Trends in Cell Biology, a Cell Press journal.

Impacts so far

Based on our findings, we have filed a patent for IL1RAP CAR-T cell therapy in human cancers.

Potential future influence

Based on our findings, we may initiate clinical trials in the near future to target IL1RAP with immunotherapeutic strategies, including highly specific chimeric antigen receptor (CAR) T cells and antibody-drug conjugates.

Next steps

We aim to develop various immunotherapeutic strategies to target IL1RAP in human cancers, including highly specific chimeric antigen receptor (CAR) T cells and antibody-drug conjugates.

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