Modulation of anti-tumour immunity using CDK4/6 inhibitors

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Published: 14 Dec 2018
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Dr Shom Goel - Dana-Farber Cancer Institute, Boston, USA

Dr Shom Goel speaks to ecancer at SABCS 2018 about the modulation of anti-tumour immunity using CDK4/6 inhibitors.

He explains that CDK4/6 inhibitors not only stop cancer cells from dividing but also aid the immune system by increasing the level the cell presents antigen and making them more visible to the immune system.

He also reports the effect to the actual immune cells as, although some of the effects can decrease the activity of T lymphocytes, other effects can cause an increase in activity, with Dr Goel believing the information gathered so far shows the positives to outweigh the negatives.
 

I had the pleasure of delivering an educational talk at the meeting today. The topic of my talk was ‘Examining the interactions between the CDK4/6 pathway and immunology in breast cancer.’ As we all know, the CDK4/6 inhibitors are a class of drug that we are now routinely using to treat patients with metastatic breast cancer. My question is, is there any role for combining these drugs with immune based therapies and that was the subject of my presentation today.

What kind of immune based therapies are you looking at?

At the moment in breast cancer we don’t really have a lot of experience with immune based therapies so I’m not really sure that I could point you in one way or the other in that regard. My main question at the moment is, what is the effect of these drugs on the tumour immune microenvironment. Mainly my laboratory research so far has shown a somewhat surprising finding which is that CDK4/6 inhibitors seem to help not only stop cancer cells from dividing but also to help the immune system fight a cancer. We’ve seen this in laboratory work done primarily in mice but we’re actually at this meeting beginning to see some emerging data from patients to suggest that this may actually be happening in the clinic as well.

What kind of mechanism is coming from these CDK4/6 inhibitors that is actually triggering the immune system?

That’s a great question and, broadly speaking, we can divide it into two buckets. The first is what are the effects of these drugs on tumour cells and then the second is what is the effect of these drugs on immune cells. So when it comes to tumour cells we usually think about these drugs as working by stopping tumour cells from dividing and certainly that is a big part of what they do. However, what we have found, and others have subsequently found in the lab, is that there is another thing that these drugs can do to tumour cells and that is increase the level to which they can so-called present antigen on the cell surface therefore making them more recognisable to the immune system. When it comes to the effects of the drugs on immune cells, and I’m really specifically talking about T lymphocytes, it’s a little bit more complicated. There are some things that these drugs do that could actually make T lymphocytes a little bit less active, primarily by stopping them from dividing, however it’s now becoming clear that there are many things that these drugs can do to make T lymphocytes more active and more functional.

When you put all this together into a living animal, we do our work primarily in mice, and you treat a mixture of tumour cells and T-cells all together, the question really is what is the net result – do the positive forces outweigh the negative forces? In our experience to date, and others, it actually seems like the overall result is an increase in the anti-tumour immune response.

What are the next steps?

Now we’ve got a series of laboratory studies that suggest that this phenomenon is real, at least in the lab, so the next question is how to test this in the clinic. It turns out there have already been some phase I clinical trials looking at combinations of CDK4/6 inhibitors with immune therapy in patients with metastatic breast cancer. The immune therapy that has been studied the most are antibodies that block the PD-1/PD-L1 pathway. Now these studies are very early and we can’t take the data from these studies to tell you whether this is an effective treatment or not but what I can say is that when you give these two classes of drugs together it’s very safe and very, very early data suggests that response rates are very encouraging.

The question now is how can we as a community work together to design the right clinical trial that’s going to definitively answer the question of whether immune therapies should be added to CDK4/6 inhibitors. This is going to have to be a randomised controlled trial if it’s going to be done and the key is going to be identifying the right group of patients for this approach. We have to remember that oestrogen receptor positive breast cancer, which is where we normally use CDK4/6 inhibitors is not a disease where we think there is a huge amount of immune activation going on at baseline. So if we select a group of tumours that are not using immune evasion in the first place it’s hard to know whether trying to increase immune activity is going to be effective.

What is the take home message?

The most important lesson that I hope people learn from my talk today is that CDK4/6 inhibitors could potentially enhance anti-tumour immune responses. All the research that has gone on in laboratories around the world to demonstrate this phenomenon has been published within the last twelve months and so it is still a very new concept. At the moment a lot of people are very concerned about the fact that these drugs could suppress the proliferation of T-cells and therefore make immune therapy work less well. But our laboratory work, and others, has suggested that there is another side to the coin. So if people have left my talk today understanding that the issue is more nuanced and something that we need to explore further then I’ve done my job.