Promising clinical and preclinical insights for pancreatic cancer therapy unveiled.

PDAC is one of the cancer forms with the highest medical need. The incidence is increasing, and the survival is poor. A major clinical challenge in PDAC is its distinct and protective tumor microenvironment (TME), which shields the tumor from the immune system and facilitates tumor growth, metastasis, and resistance to therapy. The crosstalk between cancer cells and cancer-associated fibroblasts (CAFs) plays a pivotal role in shaping this TME.

The IL-1 family, through IL1RAP, helps activate CAFs, which attract myeloid immune cells like monocytes and neutrophils into the tumor. This study reveals that nadunolimab blocks this process by inhibiting IL1RAP, reducing the number of immune cells recruited, which weakens the tumor's defenses. Through its other mechanism of action (ADCC), nadunolimab enhances tumor destruction.

The relevance of these preclinical results could be linked to clinical results using nadunolimab monotherapy in the CANFOUR study. In late stage metastatic PDAC patients, high tumor baseline levels of IL1RAP strongly correlate with increased progression free survival and a trend for survival advantage with a follow up of 11.5 months. This is in line with previous published results examining nadunolimab with chemotherapies, gemcitabine and nab-paclitaxel, which showed promising efficacy in first line IL1RAP-high PDAC patients.

These findings strongly signify the clinical relevance of targeting IL1RAP in PDAC using nadunolimab. This is particularly noteworthy since IL1RAP is considered as a prognostic marker where high IL1RAP expression is linked to shorter survival in PDAC patients.

This study used data from the Pancreatic Cancer Action Network's (PanCAN) Know Your Tumor precision medicine program as a validation dataset, accessed through the PanCAN SPARK health data platform. This dataset was used to study the impact of IL1RAP expression in PDAC and revealed IL1RAP as a prognostic marker.