The Potential of CAR T Cell Therapy in Pancreatic Cancer

Abstract

Pancreatic cancer has a dismal prognosis and effective treatment options are limited. It is projected to be the second most common cause of cancer related mortality in the United States by 2030 and there is urgent unmet need for novel systemic treatment options. Immunotherapy with antibodies targeting PD-1, PD-L1, CTLA-4 has not shown clinical activity in unselected pancreatic cancer, emphasizing the need for combination immunotherapy approaches or other therapeutic strategies. As such, chimeric antigen receptor (CAR) T cell therapy represents an emerging therapeutic option for pancreatic cancer. This modality utilizes genetically engineered T cells that are redirected to specific cancer-associated antigens to elicit potent cytotoxic activity. This review summarizes the available preclinical data and highlights early phase clinical trials using CAR T cell approaches in pancreatic cancer, a disease state that is gaining attention as a conduit for cell therapy. Future directions in application of CAR T cell therapy are also considered including its ability to be directed against novel epitopes and combined with other therapeutic regimens.

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

“…ACT with genetically engineered cells CAR-engineered T cell (CAR-T) ACT for PDAC was very recently thoroughly reviewed [127][128][129][130][131]. Various artificial gene-design strategies targeting the cancer stroma and overcoming immunosuppressive factors have been explored to improve the effect of CAR-T ACT on PDAC.…”

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

“…In addition to chemotherapy and radiotherapy, immunotherapy and targeted therapy are emerging as remarkable anticancer strategies [8][9][10]. Nevertheless, many successful immunotherapies against other cancer types are not as effective in pancreatic cancer treatment [11,12], and most clinical trials focusing on targeted therapy fail to show satisfying outcomes [13]. Therefore, breakthroughs in pancreatic cancer treatment are needed.…”

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers

“…A number of potentially targetable HLA class I-restricted peptide antigens have been identified in PDAC, most notably those derived from carcinoembryonic antigen-related cell adhesion molecule (CEACAM), mucin 16 (MUC16), mesothelin (MSLN), and mutated KRAS , among others 26 – 30 . Although promising, therapies targeting non-mutated TAAs have faced inherent limitations, including the induction of toxicities in non-tumor tissues, low prevalence of target antigen expression, or inability to break self-tolerance mechanisms that often hinders the generation of high-affinity CTLs 20 , 31 , 32 . With limited exceptions, clinical trials targeting these antigens have yielded disappointing results, underscoring the need to identify safe, immunogenic targets that demonstrate higher prevalence in PDAC patients.…”