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30 “There are several mechanisms in place to main
tain peripheral immune tolerance, and the findings made by this year’s laureates clearly showed that the absence of FoxP3+ Tregs is enough to break tolerance in both mouse and man.” LEO HOLMGREN pressive than mice Tregs. They have also found that activated human Tregs express COX-2 and produce prostaglandin E2 (PGE2), which suppresses effector T cells in a non-contact dependent manner, whereas other modes of suppression are contact dependent, and also that, for example in colorectal cancer, Treg-mediated suppression of anti-tumor immunity occurs with PGE2. “More recent work has involved peripherally induced Tregs (as opposed to naturally occurring Tregs educated in the thymus) and their role in the tumor micro-environment. We have also established in vitro methods for how to make peripherally induced Tregs and we are using such methods in a cell-based assay to screen chemical libraries for small molecule Treg inhibitors with potential application in cancer,” says Taskén. A treatment for atopic dermatitis Although the Nobel discoveries honored this year are basic, fundamental science, there are today over 200 clinical trials involving Tregs, stated Rickard Sandberg, Associate Professor, Karolinska Institutet and Member of the Nobel Assembly at Karolinska Institutet, at the press conference after the Nobel Prize announcement – emphasizing the medical benefits on the horizon. One such medical benefit is TIRmed Pharma’s novel topical treatment for atopic dermatitis (eczema), designed to modulate the immune system through the induction of Tregs. The drug contains the active substance TIR-01, an immunomodulatory oligonucleotide that helps re-establish immune tolerance in the skin. The company, founded in 2018, is based on Professor Anna-Lena Spetz’s research at Stockholm University, entailing the discovery of a non-coding oligonucleotide that inhibits TLR3 activation by interfering with the uptake of ligands destined for endosomes. “Furthermore, her group showed that the non-coding oligonucleotide modulates the differentiation of myeloid antigen-presenting cells to become tolerogenic with the capacity to reduce T helper cell activity and promote the induction of FoxP3+ Tregs,” explains Leo Holmgren. The company is currently setting up GMP production and finalizing the GLP toxicity studies with its oligonucleotide treatment, and aims to start phase I/II studies in 2026. Exciting new treatments Nils Landegren is hopeful that in the future, therapies that enhance Treg-mediated immune tolerance will become an effective way to treat a wide range of autoimmune diseases. “At the same time, the opposite strategy, to inhibit Treg activity, could make cancer immunotherapies more powerful by allowing the immune system to attack tumors more effectively. Both directions are incredibly exciting, and together they show how understanding immune tolerance can lead to better treatments for both autoimmune and cancer patients,” he says. “In autoimmune diseases work has focused on methods to expand and activate Tregs in vivo (with Il-2) or ex vivo to get better suppression, and genetics modifications are being exposed to correct the FoxP3 mutations that cause IPEX. Tregs may also be genetically modified in cell therapy approaches to target them or to treat rheumatic diseases. In cancer, the focus has been on depleting or inhibiting Tregs to dampen suppression and restore endogenous anti-tumor immunity,” says Kjetil Taskén. “While no Treg therapies are available today I would Leo Holmgren, CEO, TIRmed Pharma expect that we will see immune therapies targeting Tregs in the future that will supplement what we have and can be combined with other treatments for immune regulation and to steer immunotherapy optimally,” he concludes. NLS THE NOBEL PRIZE // MEDICINE