Innate Immune Receptor and Co-stimulation

Harnessing the immune system's natural power for therapeutic uses involves advanced genetic engineering of innate immune cells or isolating specific receptors from these cells.

This strategy is key to unlocking the immune system's full therapeutic potential, specifically by creating an imbalance between activating and inhibitory receptors. A prime example is the use of receptors from γδT cells, which have an exceptional ability to identify and attack a broad range of tumor cells, even those with minimal mutations, while leaving healthy cells unharmed. By harvesting these receptors, researchers can develop a novel category of engineered immune cells, known as TEGs (αβT cells engineered with a specific γδT cell receptor). This method merges the strengths of αβT cells with those of γδT cells, offering precise targeting of cancer cells without the collateral damage associated with conventional cancer therapies like chemotherapy and radiation. Moreover, genetically modifying γδT cells presents a promising strategy.

Recently, dual-targeting strategies have emerged as more adaptable and potentially more effective than some treatments in early clinical trials. These strategies employ a primary activation signal alongside a secondary co-stimulatory signal to finely tune activation, thereby avoiding immune cell exhaustion—a frequent drawback of certain therapies that can diminish their long-term effectiveness. Research into the molecular dynamics of these engineered immune cells has provided valuable insights into making them more resilient and less prone to exhaustion. Modifying the cells' reaction patterns can result in immune cells that have the power to maintain tumor control over extended periods

References

·      Translating γδT cells and their receptors into cancer cell therapies. Nature Reviews Drug Discovery  2020

·      Dual targeting of cancer metabolome and stress antigens affects transcriptomic heterogeneity and efficacy of engineered T-cells Nature Immunology 2024