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Generation and Functional Characterization of PLAP CAR-T Cells against Cervical Cancer Cells
Vahid Yekehfallah1,2, Saghar Pahlavanneshan3, Ali Sayadmanesh2,4
1School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
Abstract:
Chimeric antigen receptor (CAR) T-cell therapy is one of the cancer treatment modalities that has recently shown promising results in treating hematopoietic malignancies. However, one of the obstacles that need to be addressed in solid tumors is the on-target and off-tumor cytotoxicity due to the lack of specific tumor antigens with low expression in healthy cells. Placental alkaline phosphatase (PLAP) is a shared placenta- and tumor-associated antigen (TAA) that is expressed in ovarian, cervical, colorectal, and prostate cancers and is negligible in normal cells. In this study, we constructed second-generation CAR T cells with a fully human scFv against PLAP antigen andthen evaluated the characteristics of PLAP CAR T cells in terms of tonic signaling and differentiation in comparison with ΔPLAP CAR T cells and CD19 CAR T cells. In addition, by co-culturing PLAP CAR T cells with HeLa and CaSki cells, we analyzed the tumor-killing functions and the secretion of anti-tumor molecules. Results showed that PLAP CAR T cells not only proliferated during co-culture with cancer cells but also eliminated them in vitro. We also observed increased secretion of IL-2, granzyme A, and IFN-γ by PLAP CAR T cells upon exposure to the target cells. In conclusion, PLAP CAR T cells are potential candidates for further investigation in cervical cancer and, potentially, other solid tumors.
Insights
Chimeric antigen receptor (CAR) T-cell therapy shows promise for solid tumors. Researchers developed PLAP CAR T cells that effectively target and eliminate cancer cells in vitro, indicating potential for cervical cancer treatment.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is effective against blood cancers but faces challenges in solid tumors due to antigen specificity.
- Placental alkaline phosphatase (PLAP) is a tumor-associated antigen (TAA) found in various cancers (ovarian, cervical, colorectal, prostate) with minimal expression in healthy tissues.
Purpose of the Study:
- To construct and evaluate second-generation CAR T cells targeting PLAP for potential solid tumor immunotherapy.
- To assess the characteristics, tumor-killing functions, and cytokine secretion of PLAP CAR T cells.
Main Methods:
- Developed fully human scFv-based second-generation CAR T cells targeting PLAP.
- Compared PLAP CAR T cells with control CAR T cells (ΔPLAP CAR and CD19 CAR).
- Co-cultured PLAP CAR T cells with cervical cancer cell lines (HeLa, CaSki) to analyze cytotoxicity and cytokine release.
Main Results:
- PLAP CAR T cells demonstrated proliferation and effective in vitro elimination of cancer cells.
- Increased secretion of IL-2, granzyme A, and IFN-γ was observed upon target cell exposure.
- PLAP CAR T cells exhibited favorable tonic signaling and differentiation profiles.
Conclusions:
- PLAP CAR T cells are a promising candidate for treating cervical cancer and potentially other solid tumors expressing PLAP.
- Further investigation into PLAP-targeted CAR T-cell therapy is warranted for solid tumor applications.
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