IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas

Area of Science:

• Oncology
• Immunotherapy
• Cell Therapy

Background:

• Sarcomas, particularly metastatic or recurrent forms, have a poor prognosis, necessitating novel therapeutic strategies.
• Current treatment options for advanced sarcomas are limited, highlighting the urgent need for innovative targeted therapies.

Purpose of the Study:

• To evaluate the therapeutic potential of chimeric antigen receptor (CAR) T cells targeting type I insulin-like growth factor receptor (IGF1R) and tyrosine kinase-like orphan receptor 1 (ROR1) against various sarcoma types.
• To assess the expression of IGF1R and ROR1 in sarcoma cell lines and patient-derived samples.

Main Methods:

• Assessed IGF1R and ROR1 expression in multiple sarcoma cell lines.
• Generated IGF1R and ROR1 CAR T cells from healthy donors and sarcoma patients using the Sleeping Beauty (SB) transposon system.
• Evaluated CAR T cell cytotoxicity and cytokine production (IFN-γ, TNF-α, IL-13) in vitro.
• Tested the efficacy of adoptive transfer of CAR T cells in preclinical xenograft models of osteosarcoma and localized sarcoma in immunodeficient mice.

Main Results:

• High expression of IGF1R (15/15) and ROR1 (11/15) was observed in diverse sarcoma cell lines.
• IGF1R and ROR1 CAR T cells demonstrated antigen-specific cytotoxicity and cytokine release against sarcoma cells in vitro.
• Adoptive transfer of patient-derived IGF1R and ROR1 CAR T cells significantly inhibited tumor growth in preclinical models.
• CAR T cell infusion prolonged survival in mice bearing localized sarcomas.

Conclusions:

• Both IGF1R and ROR1 are viable targets for CAR T cell therapy in sarcomas.
• SB-modified CAR T cells targeting IGF1R and ROR1 show significant therapeutic potential for high-risk sarcoma patients.
• Further clinical investigation of IGF1R and ROR1 CAR T cells is warranted for sarcoma treatment.