Targeting T regs in tumours
Dr Dario Vignali - University of Pittsburgh School of Medicine, Pittsburgh, USA
A lot of my work is focussed on regulatory T-cells, these are a small population of CD4 cells endowed with very potent suppressive capacity. They play a key role in preventing autoimmunity inflammatory disease, so they play a key role in modulating and maintaining a healthy immune system. Any person that has a defect in regulatory T-cells such as IPEX will get a spontaneous autoimmune disease so they’re really important cells but, by the same token, patients that have IPEX that receive a bone marrow transplant completely restore their immune function. So they both have significant consequences if they’re not present but also great potential restorative capabilities if restored.
Unfortunately, even though they play this key homeostatic role, they are upregulated or enhanced in a number of diseases, particularly in cancer, and therefore they represent a major barrier to effective anti-tumour immunity. That has been demonstrated in mouse models of human cancer and a lot of clinical trial data showing correlates between increased regulatory T-cells with either poor prognosis or poor response to some therapeutic treatments.
What advances are you seeing towards treatments?
There’s obviously enormous interest and excitement about the efficacy that has been seen with checkpoint inhibition, anti-CTLA4 and anti-PD-1 are obviously in the clinic. Of course there’s inevitably a lot of attention to additional checkpoint inhibitors, LAG-3 was the next one in the clinic. Actually that’s something that we have particular interest because we’ve been working on LAG-3 for over fifteen years, probably published more papers on LAG-3 than most other groups, so we’re very interested in that. But clearly a lot of people are thinking beyond checkpoint inhibition. Obviously people are interested in trying to upregulate co-stimulation through agonist activation but with regard to the focus of my talk and what we’re discussing here, people are also trying to find ways to manipulate regulatory T-cells as well as other inhibitory populations. But that’s further behind with regard to clinical development but there are three or four ways one could think about modulating them: firstly by modulating their capacity to migrate into the tumour and, indeed, that’s probably the first thing that’s in the clinic. A molecule called CCR4 is a chemokine receptor, it basically functions to guide a cell where it migrates. A lot of tumours will make high amounts of the ligands for CCR4, therefore attracting regulatory T-cells into the tumour microenvironment and thereby helping to protect them against the immune system. So an antibody to CCR4, mogamulizumab, is in clinical trials at the moment; too early to say how efficacious it will be but that will be interesting to see if that is an effective modality.
A lot of academic groups and companies are also developing therapies against either effector mechanisms or suppressive mechanisms that regulatory T-cells use or other pathways that might generally undermine regulatory T-cell function in a selective way to obviously not impact the tumour specific T-cells. Of course the other important thing about any therapy that targets regulatory T-cells is it really has to be relatively restricted to the tumour microenvironment because obviously a substantive effect on the general regulatory T-cell pool may induce autoimmune or inflammatory disease. So it has to be quite surgical and a lot of efforts are going in that direction. In the next five to ten years, hopefully sooner, we’ll get a sense of whether that’s an effective strategy to combine with all of the new developments that are coming along the pipeline for cancer immunotherapy.
Are there any combinations of regulating T-cells alongside other checkpoint inhibitors?
There’s almost a bewildering number of combinations that have been tried at the moment. And certainly people are trying to combine checkpoint inhibition with conventional chemotherapy or radiotherapy. I think the general goal or mindset is to not just simply combine things that are similar, although that has shown to be efficacious, so PD-1 and CTLA-4 are both checkpoint inhibitors but have shown efficacy by combining. But most people believe that if you can combine therapies that target things in quite different ways that will be efficacious. So there has certainly been efficacy seen with checkpoint inhibition plus chemotherapy and also radiotherapy. We shouldn’t also leave out vaccination; DC vaccines have been in the clinic for a while and those are being combined with checkpoint inhibition. Very recently people have become excited about the potential of oncolytic viruses to not only target the tumour and modulate the tumour microenvironment but an opportunity to deliver so-called payloads that could modulate the immune system further.
What is your take-home message?
Suffice to say that regulatory T-cells are an amazingly exciting population of immune cells endowed with very potent properties that could be either targeted for therapy in cancer. But, of course, we shouldn’t ignore the other side of the equation which is that they are obviously being studied extensively to see how their activity could be enhanced to treat autoimmune and inflammatory disease. So a lot of the research is being done to focus on understanding these pathways in cancer, particularly because regulatory T-cells and inhibitory receptors that are most upregulated in cancer could have beneficial consequences far beyond cancer in terms of deriving therapies for many other diseases.