Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T-cell-based immunotherapy
| Autor: | Iulia Diaconu, Tristan Holland, Lisa J Pechilis, Kenneth P Ganley, Daniel Sommermeyer, Kathrin Davari, Giulia Longinotti, Prashant R Nambiar, Laura Prassmayer, Dolores J. Schendel, Christian Ellinger, Michael S. Magee |
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| Rok vydání: | 2021 |
| Předmět: |
Cytotoxicity
Immunologic Cancer Research Adoptive cell transfer Priming (immunology) Mice SCID CD8-Positive T-Lymphocytes Immunotherapy Adoptive Mice Inbred NOD Neoplasms Immunology and Allergy CD154 RC254-282 Receptors Chimeric Antigen Neoplasms. Tumors. Oncology. Including cancer and carcinogens Neoplasm Proteins Tumor Burden Phenotype medicine.anatomical_structure Oncology Molecular Medicine Female immunotherapy CD4-positive T-lymphocytes CD8 Antigens T cell Immunology Antigen presentation chemical and pharmacologic phenomena Biology adoptive Antigen Antigens Neoplasm HLA-A2 Antigen medicine Animals Humans Pharmacology Immune Cell Therapies and Immune Cell Engineering Immunodominant Epitopes T-cell receptor Xenograft Model Antitumor Assays Coculture Techniques antigen presentation HEK293 Cells A549 Cells Cancer research K562 Cells CD8 |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 3 (2021) Journal for Immunotherapy of Cancer |
| ISSN: | 2051-1426 |
| DOI: | 10.1136/jitc-2020-002035 |
| Popis: | Background The cancer-testis antigen MAGE-A4 is an attractive target for T cell-based immunotherapy, especially for indications with unmet clinical need like non-small-cell lung carcinoma or triple-negative breast cancer. Overcoming high tumor burden using adoptive transfer of T cells modified to express a transgenic T cell receptor (TCR) demands optimal recognition of the corresponding target on tumor cells by the TCR-modified T cells (TCR-Ts). Here we describe the isolation and pre-clinical characterization of high avidity TCR-Ts expressing a human leucocyte antigen (HLA)-A*02:01-restricted MAGE-A4-specific TCR that is fully functional in T cells irrespective of CD4 or CD8 co-receptor expression. Methods An unbiased CD137-based sorting approach was first used to identify an immunogenic MAGE-A4-derived candidate epitope that was properly processed and presented on HLA-A2 molecules encoded by the HLA-A*02:01 allele. To isolate high avidity T cells via subsequent multimer sorting, an in vitro priming approach using HLA-A2-negative donors (allogeneic-HLA-restricted priming approach) was conducted to bypass central tolerance to this self-antigen. Pre-clinical parameters of safety and activity were assessed in a comprehensive set of in vitro and in vivo studies of the lead TCR candidate derived from a selected T cell clone. Results A TCR recognizing the MAGE-A4-derived decapeptide GVYDGREHTV was isolated from primed T cells of a non-tolerant HLA-A2-negative donor. The respective TCR-T cell product bbT485, expressing the lead TCR in T cells from healthy donors, was demonstrated pre-clinically to have a favorable safety profile and superior in vivo potency compared to TCR-Ts made using a TCR derived from an HLA-A2-positive donor bearing a tolerized T cell repertoire to self-antigens. The natural high avidity allogeneic (allo)-derived TCR was found to be CD8 co-receptor-independent, allowing effector functions to be elicited in transgenic CD4+ T helper cells. These CD4+ TCR-T cells not only supported an anti-tumor response by direct killing of MAGE-A4-positive tumor cells, but also upregulated hallmarks associated with helper function, such as CD154 expression and release of key cytokines upon tumor-specific stimulation. Conclusions The extensive pre-clinical assessment of safety and in vivo potency of this non-mutated high avidity, CD8 co-receptor-independent, MAGE-A4-specific HLA-A2 restricted TCR provide the basis for its use in clinical TCR-T immunotherapy studies. The ability of this co-receptor-independent TCR to activate all transduced T cells (irrespective of CD4 or CD8 expression) could potentially provide enhanced cellular responses in the clinical setting through the induction of functionally diverse T cell subsets that goes beyond what is currently tested in the clinic. |
| Databáze: | OpenAIRE |
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