Abstract 6429: A surrogate to the anti-IL1RAP antibody nadunolimab induces tumor microenvironment changes to the metastatic lung and reduces metastatic lesions in mouse models of metastatic cancer

Abstract Interleukin-1 Receptor Accessory Protein (IL1RAP) is a coreceptor for the IL-1 receptor (IL1R1) and is required for IL-1α and IL-1β signaling. IL1RAP is expressed in the tumor microenvironment (TME); on cancer cells, stromal cells and on infiltrating immune cells in several types of cancers, including non-small cell lung cancer (NSCLC), pancreatic cancer (PDAC), triple-negative breast cancer (TNBC) and in metastatic lesions. Nadunolimab (CAN04) is a fully humanized ADCC-enhanced IgG1 antibody targeting IL1RAP and blocking both IL-1α and IL-1β signaling, currently evaluated in combination with chemotherapy in phase I/II clinical trials in NSCLC and PDAC (NCT03267316) and in TNBC (NCT05181462). Interim efficacy data are available for PDAC and NSCLC and are stronger than expected from chemotherapy alone based on historical controls; in a total of 73 PDAC patients, median iPFS is 7.2 months and median OS 12.7 months, while in a total of 30 NSCLC patients, a response rate of 53% is achieved, resulting in median PFS of 6.8 months. Microenvironmental IL1RAP-dependent IL-1 signaling contributes to tumorigenesis, tumor invasiveness and an immune-suppressive TME, partly driven by infiltration and induction of myeloid-derived suppressor cells (MDSCs). We have thus used the MDSC-rich 4T1 murine mammary tumor TNBC model to study metastatic lesions and TME modulation in 4T1 metastatic lungs upon treatment with a mouse surrogate antibody to nadunolimab. Infiltration of gMDSC/Ly6G+ cells was very prominent in metastatic lungs from mice with orthotopically implanted 4T1 breast cancer cells compared to lungs from naive mice. Interestingly, infiltrating Ly6G+ cells from metastatic lungs had a distinctly upregulated IL1RAP expression compared to Ly6G+ cells from naïve lungs. Treatment with the nadunolimab surrogate antibody significantly reduced the number of lung metastases and induced prominent changes in the lung microenvironment where nanostring analysis showed global changes in adhesion and migration-related genes, as well as genes associated with cell activation. The effect on metastasis was not confined to the 4T1 model since a reduction of metastatic tumor cells after treatment with the mouse surrogate antibody was also observed in the murine B16-F10-luc i.v. model. Together these data indicate that targeting IL1RAP is an effective way to modulate the TME and counteract the suppressive environment in metastatic tissue, and ultimately may reduce the potential for metastatic tumors in cancer patients. Citation Format: Elin Jaensson Gyllenbäck, Camilla Rydberg Millrud, Petter Skoog, Caitríona Grönberg, David Liberg. A surrogate to the anti-IL1RAP antibody nadunolimab induces tumor microenvironment changes to the metastatic lung and reduces metastatic lesions in mouse models of metastatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6429.