Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T-cell-based immunotherapy.

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 or triple-negative breast cancer.
Methods: An unbiased CD137-based sorting approach was first used to identify an immunogenic MAGE-A4-derived epitope (GVYDGREHTV) that was properly processed and presented on human leukocyte antigen (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 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.
Results: A MAGE-A4-reactive, HLA-A2-restricted T-cell receptor (TCR) was isolated from primed T cells of an HLA-A2-negative donor. The respective TCR-T-cell (TCR-T) product bbT485 was demonstrated pre-clinically to have a favorable safety profile and superior in vivo potency compared with TCR-Ts expressing a TCR derived from a tolerized T-cell repertoire to self-antigens. This natural high-avidity TCR was found to be CD8 co-receptor independent, allowing effector functions to be elicited in transgenic CD4 ⁺ T helper cells. These CD4 ⁺ TCR-Ts supported an anti-tumor response by direct killing of MAGE-A4-positive tumor cells and upregulated hallmarks associated with helper function, such as CD154 expression and release of key cytokines on tumor-specific stimulation.
Conclusion: The extensive pre-clinical assessment of safety and in vivo potency of bbT485 provide the basis for its use in TCR-T immunotherapy studies. The ability of this non-mutated high-avidity, co-receptor-independent TCR to activate CD8 ⁺ and CD4 ⁺ T cells 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.
Competing Interests: Competing interests: KD, TH, LP, GL, DJS, DS, and CE are employees and DJS is a Managing Director of Medigene Immunotherapies GmbH, a subsidiary of Medigene AG, Planegg, Germany. CE and DS are designated as inventors on two patent applications (PCT/EP2020/058779 and PCT/US20/31796) related to this work that have been filed by Medigene Immunotherapies GmbH and bluebird bio Inc. KPG, LJP, PRN, and MSM are current employees at bluebird bio Inc., Cambridge, USA. ID was an employee of bluebird bio., Cambridge, USA during her contributions to this publication. ID is a current employee of ElevateBio, Waltham, USA. KPG, LJP, ID, PRN, and MSM are current equity holders at bluebird bio., Cambridge, USA.
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