Therapeutic effiacy of T cells expressing chimeric antigen receptor derived from a mesothelin-specific scFv in orthotopic human pancreatic cancer animal models

Abstract

Novel CAR T cells targeting mesothelin (MSLN) expressed on pancreatic cancer cells were developed to overcome the limit of the clinical efficacy of CAR T cell therapy for pancreatic cancer patients. Optimal single-chain variable fragments (scFv) binding to MSLN were selected based on the binding activity and the functional effectiveness of various scFv containing CAR-expressing T cells. Engineered MSLN CAR T cells showed successful anti-tumor activity specific to MSLN expression level. Furthermore, MSLN CAR T cells were evaluated for the anti-cancer efficacy in orthotopic mouse models bearing pancreatic cancer cells, MIA Paca-2, MSLN-overexpressed MIA Paca-2 or endogenously MSLN-expressing AsPC-1. Mice were randomized into control, mock treated, MS501 BBz treated, MS501 28z treated or MS501 28BBz treated group. Mice were monitored by weekly IVIS imaging and tumors were harvested and analyzed by immunohistochemical analyses. MSLN CAR T cells produced the therapeutic effect in orthotopic animal models with complete remission in significant number of mice. Histopathological analysis indicated that CD4+ and CD8+ MSLN CAR T cells infiltrated pancreatic tumor tissue and led to cancer cell eradication. Our results demonstrated the anti-tumor efficacy of MSLN CAR T cell therapy against pancreatic cancer, suggesting its therapeutic potential.

Comprehensive analysis of INTS family related to expression, prognosis, diagnosis and immune features in hepatocellular carcinoma

“…The tumor microenvironment (TME) plays a crucial role in the development and progression of HCC, with distinct immune features correlating significantly with response to immune therapy and tumor behavior [ 34 ]. INTS12, for instance, has been identified as a participant in the immunotherapy process for pancreatic cancer [ 35 ]. In this study, we analyzed the correlation between INTSs expression and TME scores, tumor immune cell infiltration, and immune subtypes.…”

Current and future immunotherapeutic approaches in pancreatic cancer treatment

“…CAR T cell therapy, which targets both MSLN and CD19 simultaneously, proved to be a safe and well-tolerated approach in treating individuals suffering from metastatic PDAC [ 298 ]. In orthotopic animal models of human pancreatic cancer, it was demonstrated that MSLN-specific CAR T cells are efficient [ 299 ]. Mice with extremely aggressive PDAC experience tumor shrinkage when subjected to a mixture of MSLN-redirected CAR T cells and TNF-α/IL-2-armed oncolytic adenoviruses [ 300 ].…”

Mechanisms of Action and Limitations of Monoclonal Antibodies and Single Chain Fragment Variable (scFv) in the Treatment of Cancer

“…Afterward, chimeric receptors were able to bind to their specific ligands in the tumor cells and trigger the signal activation for activating CD8+ T cells and releasing cytokines, chemokines, and proteases [ 103 ] ( Figure 5 A). This type of therapy was one of the most promising, with several clinical trials in development, including for pancreatic cancer [ 141 , 142 ], ovarian cancer [ 143 ], and leukemia, in which CAR T cells were directed against targets such as CD70 [ 144 , 145 ] and CD19 [ 146 , 147 ] ( Table 2 ).…”