Blockade of IL-1 alpha and IL-1 beta signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy

IL-1 alpha and IL-1 beta are both involved in several aspects of tumor biology, including tumor initiation, progression, metastasis, and not least in resistance to various therapies. IL-1 alpha can function as an alarmin to signal cellular stress, and acts to induce downstream events, including production of IL-1 beta, to amplify the signal. Both IL-1 alpha and IL-1 beta act through the same receptor complex, IL-1R1-IL1RAP, to mediate signal transduction. IL1RAP is expressed on tumor cells and in the tumor microenvironment by for example CAF, macrophages and endothelial cells. The anti-IL1RAP antibody nadunolimab (CAN04) inhibits both IL-1 alpha and IL-1 beta signaling and induces ADCC of IL1RAP-expressing tumor cells. As both IL-1 alpha and IL-1 beta mediate chemoresistance, the aim of this study was to explore the potential synergy between nadunolimab and chemotherapy. This was performed using the NSCLC PDX model LU2503 and the syngeneic MC38 model, in addition to in vitro cell line experiments. We show that chemotherapy induces expression and release of IL-1 alpha from tumor cells and production of IL-1 beta-converting enzyme, ICE, in the tumor stroma. IL-1 alpha is also demonstrated to act on stromal cells to further induce the secretion of IL-1 beta, an effect disrupted by nadunolimab. Nadunolimab, and its surrogate antibody, synergize with platinum-based as well as non-platinum-based chemotherapy to induce potent anti-tumor effects, while blockade of only IL-1 beta signaling by anti-IL-1 beta antibody does not achieve this effect. In conclusion, blockade of IL1RAP with nadunolimab reduces IL-1-induced chemoresistance of tumors.