Vall d'Hebron Talks by VHIR 'ABTL0812 mitigates the immunosuppressive TME of pancreatic cancer by targeting pro-tumoral Treg cells, M2 macrophages and stroma'

Speaker: Dr. Lorena Usero Redrejo, Postdoctoral Researcher Protein Kinases in Cancer Research Laboratory. Vall d'Hebron Research Institut (VHIR). Institute of Neurosciences Universitat Autònoma de Barcelona (UAB)

Pancreatic cancer (PCa) is a devastating disease with a 5-year survival rate of only 12%. Standard treatments include chemotherapy regimens such as FOLFIRINOX or gemcitabine/nab-paclitaxel, but these offer limited benefit due to high resistance rates and severe toxicity, highlighting the urgent need for novel therapeutic strategies. PCa is characterized by a highly complex and immunosuppressive tumor microenvironment (TME), composed of both cellular and stromal elements. The TME is enriched with immunosuppressive immune cells, particularly regulatory T cells (Tregs) and M2 macrophages, which suppress antitumor immunity and promote tumor progression. In addition, a dense and fibrotic stroma protects PCa tumors from various treatments, including immunotherapy, by releasing immunosuppressive cytokines and chemokines such as TGF-â and CXCL12. This creates both a physical and biochemical barrier to effective treatment. Collectively, this unique TME renders PCa a "cold" tumor that remains largely unresponsive to current immunotherapies.
ABTL0812 is a first-in-class anticancer molecule that has completed Phase 2b clinical trials, demonstrating a good safety profile and promising efficacy in advanced endometrial cancer and squamous non-small cell lung cancer (NSCLC) when combined with chemotherapy. Mechanistically, ABTL0812 induces sustained endoplasmic reticulum stress and activates the unfolded protein response (UPR) in cancer cells—without affecting non-tumoral cells—leading to autophagy-mediated apoptotic cell death.
In this talk, I will present our results on ABTL0812 in preclinical models of PCa, which support the ongoing Phase 2b clinical trial in combination with FOLFIRINOX for advanced PCa. Notably, ABTL0812 mitigates the immunosuppressive TME of PCa tumors through two mechanisms: (a) reducing tumor infiltration by immunosuppressive regulatory T cells and M2 macrophages; and (b) inhibiting the secretion of TGF-â and CXCL12 by key stromal components, such as pancreatic stellate cells and cancer-associated fibroblasts (CAFs).

Host: Dr. José Miguel Lizcano De Vega, Head, Protein Kinases in Cancer Research Laboratory. Vall Hebron Hospital Research Institute (VHIR)