Immune tolerance, which is also known as central and peripheral tolerance, is the active state of unresponsiveness of the immune system to specific substances or tissues to prevent autoimmune diseases. The process of negative and positive selection play a significant role in the development of central tolerance, where the immune system learns to discriminate between self and non-self.
Positive selection is the elimination of T cells lacking proper binding of the T- cell receptor (TCR) to the human leukocyte antigen (HLA). Conversely, negative selection eliminates high-affinity TCRs from the T cell repertoire with a very strong binding to any self-antigens, including cancer-testis antigens (CTAs), to avoid auto-immunity. Negative selection ensures that T cells that could initiate a potent autoimmune response are eliminated while the ability to recognize foreign antigens is preserved. However, only low affinity TCRs against self-antigens like cancer testis antigens are naturally circulating because of this process. These TCRs have an insufficient functional activity to target and kill any emergent tumor expressing these CTAs.
Hence, central tolerance presents a significant challenge in the isolation of high-affinity natural TCRs with improved sensitivity and safety to generate effective anti-tumor reactivity.
Medigene’s proprietary Allo-HLA T cell priming bypasses central tolerance by using a non-tolerized, un-selected T cell repertoire from a donor negative for the HLA of interest. Adding and expressing the allogeneic (Allo) HLA in the patients Antigen Presenting Cells (APCs) for T cell priming has the potential to access naturally high-affinity TCRs for better safety and tumor reactivity (Figure 1). For this reason, Medigene does not need to mutate the TCR to increase sensitivity, specificity or affinity. Medigene relies on nature to provide the optimal affinity TCRs. Allo-primed TCR-T cells recognize tumor cells expressing varying levels of MAGE-A4 mRNA with higher sensitivity vs. Auto-primed TCR-T cells (Figure 2).
Figure 1:
Medigene’s proprietary Allo-HLA T cell priming
Figure 2:
Sensitivity of different tumor cells comparing Auto TCR vs. Allo TCR
Allo-primed TCR-T cells show rapid anti-tumor activity without signs of relapse, measured up to day 37, vs. Auto-primed TCR-T cells (Figure 3).
Figure 3:
Comparison of Auto TCR vs. Allo TCR in vivo
Medigene is able to then select these naturally occurring, highly sensitive, highly specific, optimal affinity TCRs which provides confidence our TCRs will be effective and safe.