Despite some remarkable patient outcomes in recent years, most tumours do not respond to immune checkpoint inhibitors (such as nivolumab and ipilimumab), or they develop resistance to these treatments. However, researchers at Johns Hopkins University in Baltimore, USA, have developed a new class of cancer immunotherapy agents designed to disrupt the key mechanisms whereby tumours evade attack by the immune system.
The research, published in Nature Communications, investigates the actions of a cytokine called transforming growth factor-β (TGFβ), which is involved in a complex web of cellular processes, and regulatory T cells (Tregs). TGFβ is produced by cancer cells to help the cancer avoid attack by the immune system. TGFβ also stimulates the development of Tregs to block other immune cells from attacking the tumour.
The researchers have developed a new type of immunotherapy called bifunctional antibody-ligand traps (Y-traps) to block the action of TGFβ on Tregs. They engineered Y-traps composed of an antibody targeting either CTLA-4 or PD-L1, joined with an antibody blocking TGFβ. These Y-traps are designed to stop the action of TGFβ on Tregs, and enhance the efficacy of immune checkpoint inhibitors.
Y-traps are extremely versatile and can be developed to address the myriad of ways in which cancers evade the immune system and induce immune tolerance. “We have developed Y-traps that address the most pressing mechanisms of immune dysfunction in cancer, including T cell exhaustion and tumour-promoting inflammation in the tumour microenvironment,” says Dr Bedi, lead researcher at John Hopkins University. These Y-traps could become a new generation of immunotherapies that help to unlock the immune system and overtake current immune checkpoint inhibitors.
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