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Updated: Aug 15, 2025
A Nonviral Approach to Generate Transient Chimeric Antigen Receptor T Cells Using mRNA for Cancer Immunotherapy
Published on: February 21, 2025
A library of cancer testis specific T cell receptors for T cell receptor gene therapy
Marije A J de Rooij1, Dennis F G Remst1, Dirk M van der Steen1
1Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
Abstract:
To increase the number of cancer patients that can be treated with T cell receptor (TCR) gene therapy, we aimed to identify a set of high-affinity cancer-specific TCRs targeting different melanoma-associated antigens (MAGEs). In this study, peptides derived from MAGE genes with tumor-specific expression pattern were identified by human leukocyte antigen (HLA) peptidomics. Next, peptide-HLA tetramers were generated, and used to sort MAGE-specific CD8+ T cell clones from the allogeneic (allo) HLA repertoire of healthy donors. To evaluate the clinical potential, most potent TCRs were sequenced, transferred into peripheral blood-derived CD8+ T cells, and tested for antitumor efficacy. In total we identified, seven MAGE-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6, and MAGE-A9 in the context of HLA-A∗01:01, -A∗02:01, -A∗03:01, -B∗07:02, -B∗35:01, or -C∗07:02. TCR gene transfer into CD8⁺ T cells resulted in efficient reactivity against a variety of different tumor types, while no cross-reactivity was detected. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells were observed in the orthotopic xenograft model for established multiple myeloma. The identification of seven MAGE-specific TCRs expands the pool of cancer patients eligible for TCR gene therapy and increases possibilities for personalized TCR gene therapy.
Insights
Researchers identified seven T cell receptor (TCR) therapies targeting melanoma-associated antigens (MAGEs). These TCRs show potent antitumor effects, expanding eligibility for cancer gene therapy and enabling personalized treatments.
Area of Science:
- Immunology
- Oncology
- Gene Therapy
Background:
- T cell receptor (TCR) gene therapy offers a promising avenue for cancer treatment.
- Expanding the repertoire of cancer-specific TCRs is crucial for broader patient eligibility.
- Melanoma-associated antigens (MAGEs) are key targets for cancer immunotherapy.
Purpose of the Study:
- To identify high-affinity, cancer-specific TCRs targeting MAGEs for enhanced TCR gene therapy.
- To evaluate the clinical potential and antitumor efficacy of newly identified TCRs.
Main Methods:
- Human leukocyte antigen (HLA) peptidomics to identify MAGE-derived peptides.
- Peptide-HLA tetramer generation for sorting MAGE-specific CD8+ T cell clones.
- TCR sequencing, gene transfer into CD8+ T cells, and in vitro/in vivo efficacy testing.
Main Results:
- Seven MAGE-specific TCRs were identified, targeting MAGE-A1, -A3, -A6, and -A9 across various HLA types.
- Engineered T cells demonstrated potent and specific antitumor reactivity against diverse tumor types.
- Significant in vivo antitumor effects were observed in a multiple myeloma xenograft model using MAGE-A1 specific TCRs.
Conclusions:
- The identified MAGE-specific TCRs significantly expand the patient pool eligible for TCR gene therapy.
- These TCRs enhance the potential for developing personalized cancer gene therapies.
- The findings provide a foundation for novel immunotherapeutic strategies against MAGE-expressing cancers.
