About 130 years ago, American physician William Coley injected a terminally ill cancer patient with a lethal cocktail of bacteria directly into his tumour. The patient developed a high fever and, miraculously, the tumour completely regressed. Cancer immunotherapy – the use of the immune system to fight cancer – was born.
Friend or foe?
Our immune system offers us comprehensive protection against many foreign substances, bacteria, viruses and damaged cells. The working principle is simple: it distinguishes 'self' from 'foreign', i.e., between "healthy" and 'sick'. This task is performed by special white blood cells called T cells. Unfortunately, cancer cells often slip through this net. However, there are specialized T cells, known as cytotoxic T cells or T killer cells, that recognize cancer-specific structures on malignant cells with highly sensitive receptors and trigger their death.
How cancer cells trick the immune system
Unfortunately, cancer cells have developed a number of strategies to escape the T killer cells and thus our immune system. On the one hand, the malignant cells can camouflage themselves as healthy cells by adapting the cancer-typical structures on their surface. On the other hand, they can slow down the immune system by deactivating T cells. To do this, they release certain signalling substances such as prostaglandins or metabolic products such as lactate, which curb T-cell activity. Cancer cells can also completely slow down the immune response by activating immune checkpoints on the T-cells, which normally prevent an excessive reaction of the immune system – an autoimmune reaction. Modern immunotherapies aim to counteract these mechanisms and reactivate the immune system.
Releasing cancer-protecting 'brakes'
Immunotherapies with checkpoint inhibitors release the cancer-protecting 'brakes' in the immune system and are already being used to treat many types of tumours, such as melanoma, lung, colon and breast cancer. Unfortunately, they benefit only a subset of patients and resistance frequently emerges. Pre-clinical studies have shown that combining checkpoint inhibitors with blockers of the immunomodulatory enzyme indoleamine 2,3 dioxygenase 1 (IDO1) markedly improves efficacy. IDO1 is barely present in normal tissue but is abundant in many tumours, where it converts the amino acid tryptophan into kynurenine. This metabolic shift suppresses the immune response by reducing the number and activity of killer T cells.
Innovative test identifies new active substances
In their search for new inhibitors of IDO1, the team led by Herbert Waldmann and Slava Ziegler developed a novel cell-based assay that quantifies IDO1 activity by measuring the conversion of tryptophan to kynurenine in cultured cells. Screening a library of over 150,000 compounds yielded several highly potent inhibitors with diverse mechanisms, including many direct IDO1 inhibitors. In the meanwhile, a late-stage Phase 3 trial involving thousands of patients showed no clinical benefit from combining checkpoint inhibitors with conventional IDO inhibitors after all.
IDO1 receives the cellular 'kiss of death'
The failure of the trial is not fully understood, but one plausible explanation is that IDO1 can exert its cancer-promoting effect even when inhibited, simply by its presence. The researchers found that many known IDO1 inhibitors actually increase the amount of IDO1 protein, which would further enhance tumour protection. In their current study, the Dortmund researchers have now identified a new class of molecules – iDegs (IDO1 degraders)) that circumvent this problem by specifically degrading IDO1. Together with researchers from Vienna, they were able to elucidate the unique mode of action of iDegs: binding to IDO1 induces a conformational change that flags the enzyme with ubiquitin, the cell's "kiss of death". The ubiquitinated IDO1 is then recognized by the E3 ligase CRL2KLHDC3, which directs it to the proteasome for degradation.
A new hope?
"The IDO1 degraders we have discovered act by eliminating the protein rather than merely inhibiting it. This unique mechanism could overcome the limitations of previous IDO1 inhibitors and open new avenues for enhancing checkpoint‑based immunotherapy," emphasizes Waldmann. In a further publication, the scientists were able to show that iDegs inhibit tumour growth in mice with SKOV-3 tumours, leading to prolonged survival.
And the potential of IDO1 inhibitors may well be greater than previously thought: The latest studies suggest that IDO1 modulation may also benefit diseases linked to Epstein-Barr virus, as well as Alzheimer's disease. Despite earlier setbacks, interest in IDO modulators remains very high: ten active clinical IDO-1 studies are currently active, with three more in the pipeline.
