Our immune system is a complex and finely tuned fighting force, primed to recognise pathological cells or microorganisms in our body that don’t belong and destroy them. Tapping into these natural defenders — and training them to act against tumour cells — is the idea behind cancer immunotherapy.
Unfortunately, cancer immunotherapy does not yet work for everyone — sometimes, it does not effectively fight tumours, and sometimes, it causes the immune system to dangerously overreact. But our scientists at Roche are on the case, designing a new immunotherapy that hopefully better targets the right cells to provoke an immune response against the tumour.
Two new publications in Nature, co-authored by a team of Roche scientists around Pablo Umaña, Christian Klein, Laura Codarri Deak and collaborators from academia, explain why previous versions of IL-2 have not worked well in clinical trials so far. These publications describe three key new findings.
First, IL-2 has a special ability to change the fate of immune cells that recognise tumours and viruses, putting them into a new development path may lead to a more efficacious immune response. Second, it explains why the current generation of systemically delivered IL-2 mutant molecules (like IL2v) being tested in clinical trials don’t work well: by losing an interaction with one of the IL-2 receptor units through their mutation, they have lost the ability to generate this alternative immune response. Third, fusing the IL2v mutant molecule to a high-affinity PD-1 targeting molecule recovers the ability to target IL2v to the right cells and generate the more effective immune response, while maintaining the safety advantages over IL-2 of previous IL2v mutants for systemic immunotherapy in preclinical models. ”This work may provide the foundation for the next generation of hopefully more efficacious molecules that can be given systemically, and this would be an important step forward for the field,” said Pablo Umaña, who leads the cancer immunotherapy and discovery team at Roche Pharma Research & Early Development (pRED).
IL-2 is a natural molecule known as a cytokine that stimulates the immune system by binding to the three-unit IL-2 receptor on immune cells, acting locally where it is produced. At doses high enough to be effective, IL-2 often becomes highly toxic because although the molecule is meant to act at the site of an immune response, it surges through the entire body and acts on cells that it should not. At lower doses, it instead favours immunosuppressive regulatory T cells, which counteract the tumour response. Both of these undesirable effects for cancer therapy are heightened by IL-2 interacting with one of its receptor units, known as CD25. To lessen these side effects, researchers across industry and academia have been trying to develop engineered variants of IL-2 that interact less with or bypass CD25. However, these previous generations of IL-2 variants, either alone or in combination with so-called PD-1 or PD-L1 immune checkpoint inhibitors that form the cornerstone of modern cancer immunotherapy, did not improve the efficacy of the therapy.
Collaborating with Rafi Ahmed’s group at Emory University in the US, the Roche team has now explained why PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program. IL-2 and PD-1 are important signals that train the cells of the immune system to carry out particular functions — that is, follow particular “career paths”. One common end stage of a career path for T cells, a professional adaptive killer cell of the immune system, under conditions of chronic stimulation as in cancer or some viral infections, is known as exhaustion. In this case, the T cells ultimately lose their effectiveness at controlling unwanted cells. Using an animal model of chronic viral infection, the researchers showed that PD-1/PD-L1 inhibition may not reactivate exhausted cells, but rather makes them more effective earlier in their career — but they still will end up on the exhaustion “track”.
Combining PD-1 and IL-2, however, may achieve a shift to a different T cell career track more common in acute disease, where the cells are less exhausted and more effective at their job of eradicating tumour or invader pathogens. The key insight from the team is that this combination only works if IL-2 can bind to the three-part receptor including CD25 — and that IL2v, which lacks the CD25 interaction, makes this combination no more effective than PD-1 on its own, helping to explain why clinical trials thus far have not achieved success.
But the Roche team did not wait for the full explanation of why PD-1 and IL2v together were not working to try a different, more effective strategy. “We were open to following the science to do something better,” explained Christian Klein, a Distinguished Scientist who leads a team within cancer immunotherapy discovery at pRED. Together with Laura Codarri Deak, Valeria Nicolini, Masao Hashimoto, Maria Karagianni, Stefan Seeber and colleagues, Christian and Pablo present a new approach in a separate study attaching a PD-1 targeting antibody directly to IL2v, so that the combination acts on the same, tumour- or viral-antigen specific T cells. In doing so, the PD-1 targeting antibody compensates for the missing third part of the IL-2 receptor (CD25), and provokes the desired immune response in the correct cells yielding the more effective set of killer T cells, but without having the other undesirable effects of the CD25 interaction for systemic immunotherapy.
With these promising preclinical results now widely available, the team are continuing to put what they have learned to use to develop better medicines for patients. That includes the acquisition of Good Therapeutics, which has been developing a PD-1 dependent on and off switch for IL2v that can hopefully be used to generate the next generation of immunotherapies. With these programmes combined, the team hopefully continues to create ever more effective cancer immunotherapy options with less side effects. And this new way of designing molecules creates opportunities for new combinations, too. “This approach opens up a new era of how we and others may do cancer immunotherapy, and we are hoping to apply our findings beyond cancer”, commented Laura Codarri Deak, a researcher in cancer immunotherapy at pRED and first-author of Roche’s publication.