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HPB

HPB Parallel Session 2

52: Anti-HER-2 Chimeric Antigen Receptor T (CAR-T) Cells Immunotherapy for Pancreatic Cancer: An Innovative Surgically Derived Tumor Spheroid Model

Saturday, March 23, 2024
8:22am – 8:32am ET
Location: C105-106
Disclosure(s):
‪lior Orbach, MD: No financial relationships to disclose
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality and often presents as a systemic, metastatic disease with a grim prognosis and limited therapeutic options. Novel therapies are essential to improve patient survival. In this study, using an innovative 3D PDAC spheroid model, we harvested the new emerging technology of CAR-T cells to effectively target and eliminate tumor cells and withstand the immunosuppressive tumor microenvironment


Methods: Flow cytometry was used to assess the presence of the HER-2 receptor in human PDAC cell lines. Anti-HER-2 CAR-T cells were prepared by isolating PBLs, which were activated and subjected to consecutive retroviral transductions. Tumor cell cultures were treated with CAR-T cells. Interferon γ levels to evaluate CAR-T excitation were measured using ELISA. The cytotoxicity of the CAR-T cells was determined by a methylene blue staining-based assay. Fresh human PDAC tissues were obtained from patients undergoing elective surgery. Multicellular 3D PDAC spheroids were formed from human cell lines and patient-derived tumor cells and treated with anti-HER-2 CAR-T cells. Then, tumor cell death was monitored over time with live cell imaging


Results: PANC1, Mia-PaCa-2, Capan 1/2, BxPC3, and HPAF-II PDAC cell lines were assessed for the expression of HER-2 using FACS analysis. All tested PDAC cell lines expressed the HER-2 receptor to various extents. We further assessed the cytotoxicity of anti-HER-2 CAR-T cells on the indicated cells. Co-culture of anti-HER-2 CAR-T cells with target PDAC cells demonstrated effective tumor elimination with variability correlating to target: effector (T:E) ratio. At 1:30 T:E ratio, 70-90% of tumor cells were eliminated, while at 1:7.5 T:E ratio, killing rates were reduced to 10-30%. Finally, we engineered two 3D PDAC spheroids models: one consisting of HPAF-II and BxPC3 cell lines and the other formed from patient-derived pancreatic tumors. The anti-HER-2 CAR-T cells reduced effectively the spheroid size in both models


Conclusions: Our results demonstrate the effective elimination of PDAC cells with anti-HER-2 CAR-T cells. Utilization of this technology can be used as a unique treatment for PDAC. Such treatment may be administered intraperitoneally to treat either microscopic or macroscopic metastatic disease and stretch the boundaries of current surgical oncology practice. In addition, a spheroid model from patient derived tissue samples may be used as a tool for treatment effect assessment and for the development of novel therapies

Learning Objectives:

  • Describe the effect of HER-2 CAR-T cells on PC cells.
  • Understand what CAR-T cells are.
  • Understand what 3D spheroids are and their use as a research model.