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Published on: October 25, 2016
Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next
Kathrin Davari1, Tristan Holland1, Laura Prassmayer1
1Medigene Immunotherapies GmbH, Planegg-Martinsried, Germany.
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.
Insights
Researchers developed a novel T-cell receptor (TCR) therapy targeting MAGE-A4 for cancer immunotherapy. This therapy, bbT485, shows strong pre-clinical safety and efficacy, activating both CD8+ and CD4+ T cells for enhanced anti-tumor responses.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Cancer-testis antigen MAGE-A4 is a promising target for T-cell immunotherapy.
- Unmet clinical needs exist for non-small cell lung and triple-negative breast cancers.
Purpose of the Study:
- To identify and isolate a high-avidity T-cell receptor (TCR) targeting MAGE-A4.
- To pre-clinically assess the safety and efficacy of a novel TCR-T cell product (bbT485).
Main Methods:
- A CD137-based sorting approach identified a MAGE-A4 epitope (GVYDGREHTV) presented on HLA-A2.
- In vitro priming of HLA-A2-negative donors isolated a natural high-avidity TCR.
- Pre-clinical in vitro and in vivo studies assessed safety and activity of the TCR-T product bbT485.
Main Results:
- A MAGE-A4-reactive, HLA-A2-restricted TCR was isolated, leading to the TCR-T product bbT485.
- bbT485 demonstrated favorable safety and superior in vivo potency compared to TCRs from tolerized repertoires.
- The TCR is CD8 co-receptor independent, enabling effector functions in CD4+ T helper cells, which directly killed tumor cells and supported anti-tumor responses.
Conclusions:
- Extensive pre-clinical data support bbT485 for TCR-T immunotherapy studies.
- The co-receptor-independent TCR activates both CD8+ and CD4+ T cells.
- This approach may enhance clinical cellular responses through functionally diverse T-cell subsets.
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