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Published on: February 14, 2025
MMP14 is a safe target of CAR-T therapy against liver cancer and metastasis
Ye Yu1,2, Shirui Zou2, Jiawei Fan3
1West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Background:
Hepatocellular carcinoma (HCC) is one of the most lethal tumors, and effective treatments for HCC, especially metastatic HCC, are lacking. Chimeric antigen receptor (CAR)-T-cell therapy is considered a promising development in cancer treatment, but to date, CAR-T-cell therapy for solid tumors remains limited. Matrix metalloproteinase 14 (MMP14), the only membrane-bound collagenase, is highly expressed in HCC and other solid tumors and plays critical roles in invasion and metastasis.
Methods:
Here, we aimed to determine whether CAR-T cells targeting MMP14 could effectively treat HCC. CAR-T cells were designed with peptide G (PG) to specifically recognize MMP14. These cells were evaluated for their cancer-killing efficacy in vitro under MMP14-dependent conditions and tested for antitumor activity in a subcutaneous xenograft liver cancer model. Additionally, a spontaneous liver cancer metastasis model was employed to assess the impact of PG-CAR-T cells on metastasis suppression through circulating tumor cells (CTCs) elimination. The safety profile of PG-CAR-T cells was further investigated in both murine and nonhuman primate models.
Results:
PG-CAR-T cells demonstrated efficient MMP14-dependent killing of cancer cells in vitro and exhibited antitumor effects in the subcutaneous xenograft liver cancer model. In the metastasis model, PG-CAR-T cells significantly inhibited metastasis by eliminating CTCs. Furthermore, PG-CAR-T cells showed a favorable safety profile in both mice and nonhuman primates.
Conclusion:
These data support the PG-CAR-T cells for clinical trial of liver cancer.
Insights
Chimeric antigen receptor (CAR)-T cells targeting matrix metalloproteinase 14 (MMP14) show promise for treating liver cancer. These MMP14-targeting CAR-T cells effectively kill cancer cells and inhibit metastasis, with a good safety profile in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Hepatocellular carcinoma (HCC) is a lethal cancer with limited treatment options, particularly for metastatic disease.
- Chimeric antigen receptor (CAR)-T-cell therapy shows potential but faces challenges in solid tumors.
- Matrix metalloproteinase 14 (MMP14) is highly expressed in HCC and promotes tumor invasion and metastasis.
Purpose of the Study:
- To investigate the efficacy of CAR-T cells engineered to target MMP14 for HCC treatment.
- To evaluate the antitumor and antimetastatic activity of MMP14-targeting CAR-T cells.
- To assess the safety of these engineered T cells in preclinical models.
Main Methods:
- Designed CAR-T cells (PG-CAR-T) utilizing peptide G (PG) for specific MMP14 recognition.
- Assessed in vitro cancer cell killing under MMP14-dependent conditions.
- Evaluated antitumor activity in subcutaneous xenograft and spontaneous liver metastasis models.
- Investigated safety in murine and nonhuman primate models, focusing on circulating tumor cell (CTC) elimination.
Main Results:
- PG-CAR-T cells demonstrated potent MMP14-dependent cancer cell killing in vitro.
- Significant antitumor effects were observed in a subcutaneous xenograft liver cancer model.
- PG-CAR-T cells effectively suppressed metastasis by eliminating CTCs in a spontaneous metastasis model.
- A favorable safety profile was established in both mouse and nonhuman primate studies.
Conclusions:
- PG-CAR-T cells exhibit significant therapeutic potential against HCC.
- The findings support the advancement of PG-CAR-T cells into clinical trials for liver cancer treatment.
