Abstract
Pancreatic cancer has the worst prognosis and lowest survival rate among all types of cancers and thus, there exists a strong need for novel therapeutic strategies. Chimeric antigen receptor (CAR)-modified T cells present a new potential option after successful FDA-approval in hematologic malignancies, however, current CAR T cell clinical trials in pancreatic cancer failed to improve survival and were unable to demonstrate any significant response. The physical and environmental barriers created by the distinct tumor microenvironment (TME) as a result of the desmoplastic reaction in pancreatic cancer present major hurdles for CAR T cells as a viable therapeutic option in this tumor entity. Cancer cells and cancer-associated fibroblasts express extracellular matrix molecules, enzymes, and growth factors, which can attenuate CAR T cell infiltration and efficacy. Recent efforts demonstrate a niche shift where targeting the TME along CAR T cell therapy is believed or hoped to provide a substantial clinical added value to improve overall survival. This review summarizes therapeutic approaches targeting the TME and their effect on CAR T cells as well as their outcome in preclinical and clinical trials in pancreatic cancer.
Highlights
Pancreatic cancer, i.e., pancreatic ductal adenocarcinoma (PDAC), is a fatal disease with five-year overall survival rates of 1% to 5% and median survival duration of fewer than six months [1]
Pancreatic cancer represents an exceptional challenge for successful cancer therapy
Cell-based immunotherapy has shown pronounced clinical success in hematologic malignancies and its feasibility has been demonstrated in pancreatic cancer, but it needs to overcome certain barriers, such as infiltration, persistence, and exhaustion
Summary
Pancreatic cancer, i.e., pancreatic ductal adenocarcinoma (PDAC), is a fatal disease with five-year overall survival rates of 1% to 5% and median survival duration of fewer than six months [1]. Another group of artificial antigen receptors, gaining increased interest in recent years, are synNotch receptors These receptors use the cleavage process after Delta-Notch binding and enable an unlimited variety of responses (green box) after target recognition such as cell fate determination with transcription factors and expression of selected cytokines or therapeutic antibodies. In this way, they bring the potential of immune cells as “living drugs” a big step forward
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