CAR-T cell therapy: A promising frontier for pancreatic cancer treatment
Updated review highlights potential, challenges, and evolving strategies of CAR-T therapy for PDAC
image: A schematic representation of the progressive development of CAR-T cell generations from first to fourth, highlighting enhancements such as improved co-stimulatory domains, cytokine production capabilities, and multi-antigen targeting to overcome the limitations encountered in earlier versions. CAR = chimeric antigen receptor, scFv = single-chain variable fragment.
Credit: Grace El Bejjani from Lebanese American University, Lebanon Image source link: https://journals.lww.com/jpancreatology/fulltext/2026/03000/role_of_car_t_cell_therapy_in_pancreatic_cancer_.1.aspx
Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer, is projected to become the second leading cause of cancer-related deaths in the US by 2030. Conventional treatments like surgery, chemotherapy, and radiotherapy offer limited benefits, with 5-year survival rates in single digits. Immunotherapy with checkpoint inhibitors has also shown disappointing results, creating an urgent need for innovative therapies.
Chimeric antigen receptor (CAR)-T cell therapy, a form of adoptive immunotherapy, has revolutionized hematologic malignancy treatment and is now being investigated for PDAC. CAR-T cells are genetically engineered to recognize tumor antigens independently of major histocompatibility complex presentation, enabling precise cancer cell targeting. Second-generation CARs, incorporating co-stimulatory domains like CD28 or 4-1BB, are the most widely used in clinical trials.
Key targets for PDAC CAR-T therapy include mesothelin (MSLN), human epidermal growth factor receptor 2 (HER2), carcinoembryonic antigen (CEA), and Claudin 18.2 (CLDN18.2). These antigens are overexpressed in PDAC cells but have limited expression in normal tissues, reducing off-tumor toxicity risks. Early-phase clinical trials targeting these antigens have shown promising signs of disease control and manageable toxicity.
However, CAR-T therapy for PDAC faces significant challenges. The immunosuppressive tumor microenvironment (TME), dense stromal barrier, and tumor heterogeneity hinder CAR-T cell trafficking, infiltration, and persistence. Additionally, on-target, off-tumor toxicity remains a concern, as some target antigens are also expressed on healthy tissues.
To overcome these obstacles, researchers are exploring innovative strategies. Combination therapies with radiotherapy, chemotherapy, oncolytic viruses, and checkpoint inhibitors are being investigated to remodel the TME and enhance CAR-T cell efficacy. Novel CAR designs, including logic-gated and dual-receptor CARs, are being developed to improve specificity and reduce toxicity.
This updated narrative review, made available online on August 27, 2025, and published in Volume 9, Issue 1 of the Journal of Pancreatology on March 01, 2026, analyzing 74 articles from PubMed and Google Scholar, provides a comprehensive overview of CAR-T therapy's current status in PDAC treatment. It highlights the therapy's potential, key challenges, and evolving strategies, offering valuable insights for future research and clinical practice. While obstacles remain, CAR-T cell therapy represents a promising frontier in PDAC management, with ongoing research poised to improve patient outcomes.
Reference
DOI: http://doi.org/10.1097/JP9.0000000000000241
About Grace El Bejjani from Lebanese American University
Grace El Bejjani, Department of Internal Medicine, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon.