Over the past few years, progress in adoptive cell transfer (ACT) immunotherapies has accelerated, with our understanding of how they work in patients improving and this being translated into greater progress with their development and testing.
ACT treatments work by genetically engineering the patient’s killer T-cells to recognise and destroy cancer cells. There are several types, but the one that has advanced the furthest in clinical development is CAR-T, a treatment which is currently hitting the headlines.
But there is still room for improvement, not least finding ways to improve the improve the ability of the modified, transferred T cells to persist and remain functional within the patient’s body.
IL-2: a double-edged sword
Due to its involvement in the expansion, survival and activation of effector T cells, researchers have used the cytokine interleukin-2 (IL-2) alongside ACT to provide a ‘boost’ for transferred T cells. But this comes at a price: IL-2 also activates regulatory T cells and is associated with a potentially dangerous side effect called capillary leak syndrome — putting a limit on its dosage and so on its therapeutic use.
Now, a new study published in Science identifies a way of specifically harnessing IL-2’s desirable effects whilst tempering those that are unwanted.
Building on previous work determining the structure of the IL-2 receptor (IL-2R)-IL-2 complex, Sockolosky et al. generated two mutant versions of IL-2 and one of IL-2R that bind specifically to each other but not to their natural counterparts.
In both in vitro and in vivo experiments in mice, the team demonstrated that their mutant versions of IL-2 specifically expanded CD4+ and CD8+ T cells engineered to express the mutant IL-2R, but not wild-type T cells.
Reducing side effects
The researchers then went onto to investigate its potential clinical effects of using their mutant IL-2/IL-2R approach in a preclinical mouse model of melanoma.
Carrying out adoptive transfer of T cells engineered to recognise the melanoma cells, as well as express mutant IL-2R, followed by treatment with mutant IL-2, gave a similar tumour response and improvement to survival to that from treatment with T cells and wild-type IL-2. But importantly, administering mutant versions of IL-2 resulted in lower toxicity.
“The fact that we can selectively activate signalling pathways on cells expressing the orthogonal receptor in vivo without activating signalling pathways on cells native to the animal opens up the possibility that this approach could be used in adoptive cell therapy (ACT) in humans to enhance engineered or chimeric antigen receptor (CAR) T cell persistence, mitigate exhaustion and other current problems with ACT,” says Christopher Garcia, lead author of the study.
These results demonstrate a proof-of-principle for using this synthetic approach to achieve selective potentiation of engineered cells, with potential value in developing other cytokine-receptor pairs to harness the desirable signalling pathways while avoiding undesirable effects.
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- Villaneuva, MT. The perfect match. Nature Reviews Drug Discovery, published online 20 April 2018. doi:10.1038/nrd.2018.62
- Sockolosky et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptors complexes. Science 359, p1037-1042 (2018). DOI: 10.1126/science.aar3246