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Updated: May 26, 2026
Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma
N Rainusso1, V S Brawley, A Ghazi
1Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
Abstract:
Despite radical surgery and multi-agent chemotherapy, less than one third of patients with recurrent or metastatic osteosarcoma (OS) survive. The limited efficacy of current therapeutic approaches to target tumor-initiating cells (TICs) may explain this dismal outcome. The purpose of this study was to assess the impact of modified T cells expressing a human epidermal growth factor receptor (HER2)-specific chimeric antigen receptor in the OS TIC compartment of human established cell lines. Using the sarcosphere formation assay, we found that OS TICs were resistant to increasing methotrexate concentrations. In contrast, HER2-specific T cells decreased markedly sarcosphere formation capacity and the ability to generate bone tumors in immunodeficient mice after orthotopic transplantation. In vivo, administration of HER2-specific T cells significantly reduced TICs in bulky tumors as judged by decreased sarcosphere forming efficiency in OS cells isolated from explanted tumors. We demonstrate that HER2-specific T cells target drug resistant TICs in established OS cell lines, suggesting that incorporating immunotherapy into current treatment strategies for OS has the potential to improve outcomes.
Insights
Chimeric antigen receptor T cells targeting HER2 show promise against drug-resistant osteosarcoma tumor-initiating cells. This immunotherapy approach may improve survival rates for recurrent or metastatic osteosarcoma patients.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Recurrent or metastatic osteosarcoma (OS) has a poor prognosis, with less than one-third of patients surviving despite current treatments.
- Limited efficacy against tumor-initiating cells (TICs) contributes to treatment failure in osteosarcoma.
- Human epidermal growth factor receptor 2 (HER2) is a potential therapeutic target in some osteosarcoma cases.
Purpose of the Study:
- To evaluate the efficacy of HER2-specific chimeric antigen receptor (CAR) T cells against osteosarcoma TICs.
- To assess the impact of HER2-targeted immunotherapy on drug-resistant osteosarcoma cells.
Main Methods:
- Utilized sarcosphere formation assay to identify and quantify osteosarcoma TICs.
- Assessed the effect of HER2-specific CAR T cells on sarcosphere formation in vitro.
- Evaluated the in vivo efficacy of HER2-specific CAR T cells in an orthotopic mouse model of osteosarcoma.
Main Results:
- Osteosarcoma TICs demonstrated resistance to methotrexate.
- HER2-specific CAR T cells significantly reduced the sphere-forming capacity of osteosarcoma TICs.
- In vivo administration of HER2-specific CAR T cells decreased TIC populations in established tumors.
Conclusions:
- HER2-specific CAR T cells effectively target drug-resistant osteosarcoma TICs.
- Targeting HER2 with CAR T cells presents a potential strategy to overcome treatment resistance in osteosarcoma.
- Incorporating this immunotherapy may improve outcomes for patients with recurrent or metastatic osteosarcoma.
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