Immune checkpoint inhibitors

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Hi, I'm Jo Cheah, and this is the Australian Prescriber Podcast. Joining me today is Luke Ardolino. Luke is an advanced trainee in medical oncology and has written about immune checkpoint inhibitors in the Australian Prescriber. Welcome, Luke, and thanks for joining me.

Thank you. Thanks for having me.

So let's get started. Luke, could you start by explaining the immune system's normal response to a tumour, and potentially some of the mechanisms that tumours use to evade the immune system?

Yeah, of course. I think a big starting point of tumour prevention actually occurs from the inbuilt DNA damage regulation and repair mechanisms that we have in our body, and this involves p53 and numerous other tumour-suppressor genes that initially work by activating DNA repair mechanisms for abnormal cells.

Now, the damaged DNA in these malignant cells frequently caused the mutated cell to produce abnormal cell surface proteins, and these are called tumour-specific antigens. These abnormal proteins mark the cancer cell as non-self so they can be recognised by the immune system and ideally eradicated.

The immune system, the immune surveillance, sorry, is the process through which the immune system is continually assessing for these markers on cell surfaces that identify the cells as non-self, and when these are detected, this results in the specific immune response.

This is a very complicated process, but natural killer cells play a key part in this. Dendritic cells also play a role activating cytotoxic T cells. Once activated, these cells release perforins, granzymes, and they punch through the tumour cells resulting in apoptosis and appropriate tumour cell death.

This process is incredibly multifactorial. I think the complexity of it is pretty well summed up by a guy called David Lane. Now, he was one of the key investigators of the original discovery of the tumour-suppressor gene p53, and he essentially said to understand how cancers occur, you must first understand all the reasons that they do not.

The immune system itself likely encounters and eliminates malignant cells on a daily basis. However, the malignant tumours tend to occur because there's been a failure in one or more of these protective mechanisms. And this kind of brings us onto mechanisms by which tumours are able to evade the immune system.

Now, there are many, so I'll try to focus on some of the key ones, but as tumours evolve, genetic changes occur with the tumours, which can sometimes give tumours a survival advantage. One example is tumour molecules can down-regulate the major histocompatibility complex which presents the tumour-associated antigens to the immune cells. Now, if that's down-regulated or not present on the surface of tumour cells, then it means that the cells can no longer be recognised by the immune system.

Another example of tumour cells evolving to protect themselves from the immune system is the ability to express inhibitory molecules on their surface. Now, a key example of this is the expression of programmed death ligand 1, or PD-L1. Tumour cells that over-express this inhibitory molecule deactivate T cells upon binding and inappropriately result in the T cells identifying tumour cells as self or normal selves, meaning that the immune mechanisms that would normally attack these cells are no longer activated.

Thanks for that introduction. I think I asked you a big question because obviously the immune system is a whole subject on its own, and you touched on there a little bit about program death ligand, but I know that you've mentioned a couple of other pathways in your article such as CTLA-4 and PD-1. What is it about these pathways that make it possible for drugs to target these pathways to reactivate T cells?

So the first question, I suppose, is what are these pathways? I'll start with the CTLA-4 pathway. This is an inhibitory pathway. When it is activated, it down-regulates T-cell function and results in immune dampening. Interestingly, this sort of abnormal abnormalities in this pathway are thought to play a role in quite a lot of autoimmune dysfunction.

The PD-1 pathway's a lot simpler, I guess, in so that PD-1 is again inhibitory, when activated it down-regulates T-cell function, but the PD-1 molecules are expressed on T cells and the PD-L1 or PD ligands are expressed on tumour cells.

Now, tumour cells, again, manipulate this process by tending to inappropriately over-express PD-L1, meaning that there's significant amounts of PD-1 and PD-L1 binding, and then that inhibitory signal is propagated and T cells again are unable to attack these cells because they incorrectly identify them as self.

The way that these mechanisms can be targeted, with drugs, as we discussed, these are both inhibitory pathways that tumour cells have hijacked, essentially, to evade the immune system, but the drugs work by blocking these receptors and this results in a subsequent appropriate immune activation by blocking the inhibitory pathway being completed.

Ipilimumab is a fully human monoclonal antibody that binds to and inhibits the CTLA-4 receptor, and pembrolizumab and nivolumab are both fully human monoclonal antibodies that bind the PD-1 receptor, preventing it binding with its ligand PD-L1. These both result in the prevention of immune dampening effects and subsequent immune activation.

The only other two I haven't mentioned are durvalumab and avelumab. Now, both these are also monoclonal antibodies, but these rather than binding to the PD-1 receptor on the T cells actually bind to the PD-L1 receptor on the tumour cells, but it results in a very similar effect.

So can you tell us a little bit about what sort of cancers can actually be treated using these type of drugs?

Sure. The list is growing. There are many trials looking at new uses for these drugs and tending to be very successful. The tumour types of which immune checkpoint inhibitors have been most effective tended to be melanoma, non-small cell lung cancer, clear cell renal cell cancer, urothelial bladder cancers and lymphoma.

Now, what's quite interesting is this is actually predicted almost perfectly in a paper published in 2013. I think it was Nature. It basically looked at the number of somatic mutations in thousands of different tumour specimens and then plotted them from highest mutational burden to lowest. The three tumours with the highest mutational burdens were melanoma, non-small cell lung cancer and bladder cancer, and those with the lowest mutational burdens were CNS tumours, pancreatic tumours, breast cancers.

What I found really interesting is that those with the highest mutational burdens are the ones that have responded best to immunotherapies, and I like to think of it as the immune checkpoint inhibitor drugs have removed sort of the invisibility cloak that tumours have utilised to be able to evade the immune system, and then when the immune system is finally activated, it immediately targets the most mutated cells.

Maybe that's why there's so much success, but unfortunately it's a significantly more complicated process than that.

I know just from my own practice, depending on different indications, sometimes the drugs are given as weight-based or flat doses, and sometimes they're given at different frequencies or intervals. Do you have any comment on why that may be, and do you also want to comment on if there's an optimal duration for these sorts of treatments?

They are predominantly weight-based dosage protocols. Nivolumab I think is given between one and three milligrams per kilogram, pembrolizumab's a pretty standard two milligrams per kilogram, but again, these can all vary based on the protocols that they're being used in.

Again, there's also concurrent use of immunotherapy where you give ipilimumab and nivolumab in combination for four cycles and then just continue with nivolumab alone, and again the dosing changes slightly there. EviQ’s a really, really good resource for this and I'd recommend anyone sort of read through the drug information on EviQ, everything from dosing, to side effects, to management of side effects, and also the evidence base for why a lot of them are used.

You mentioned duration. Now, that's a really hot topic in medical oncology at the moment. Certainly these drugs should be continued to either the point of disease progression where they're failing to control disease, or intolerable toxicities, and both of those would be good indications for stopping these medications. But what about the group of patients who have a sustained or a complete response and are continuing to tolerate these drugs very well with minimal toxicities? Well, when do you stop?

I think either way the data's quite limited and, like I said, a lot of research still going into this. But one approach people are tending to choose at the moment is to stop the treatment after one year, provided that there has been an additional sustained response for at least six months, and then with a plan to have a low threshold for maybe restarting treatment if disease were to progress while off treatment.

Do you want to comment on any characteristics that might mean a patient can't have these types of drugs? And also we know that these drugs can cause a lot of side effects, and we'll get into it a bit later, immune-related adverse events, so do you want to maybe touch on some of the most common side effects as well?

Sure. Given immune checkpoint inhibitors work by blocking the normal mechanisms for which our bodies protect our own cells from inappropriate immune damage, the vast majority of immune-related toxicities come from inappropriate autoimmune attack on normal body tissues. Any organ system can be affected. There's almost nothing that's off limits as regard to immune-related toxicities and what can be affected.

But, common side effects tend to be skin toxicity, which can range from a rash that just blisters to, very rarely, necrosis. Thyroid toxicity's not uncommon. Hypothyroidism tends to occur much more frequently than hyperthyroidism. Endocrine toxicities occur as well, not infrequently, and these tend to be everything from pancreatic failure resulting in type 1 diabetes to hypopituitarism. Adrenal insufficiency, and adrenal insufficiency is something that I have seen quite a few times now where both adrenal glands have been completely knocked out by immunotherapy. Diarrhea is common and colitis can occur. Pulmonary toxicity with pneumonitis, and hepatotoxicity with increased transaminases and hyperbilirubinaemia. These are the sort of more common side effects that you tend to see.

I suppose it's also just worth touching on very briefly, there are non-immune-related side effects you can get with these drugs, and these tend to include anorexia, arthralgia, myalgia, fatigue, nausea, those kind of standard treatment-related side effects.

Unfortunately, at the moment, there's no current predicted markers for who will or won't tolerate immunotherapy well, and additionally there's very few predicted markers of who will actually respond and who won't respond. PD-L1 expression in lung cancer is one example which I think you touched on earlier.

However, there are a group of patients that we are very cautious about using immunotherapy in. These tend to include patients with HIV, viral hepatitis. This is really because you can get a reactivation of the hepatitis B specifically, but also poor viral load control in HIV as well. Also patients with pre-existing liver impairment, as rising transaminitis and impaired liver function tests is a common reason to stop treatment, so if the liver function's already impaired they're less likely to cope with immunotherapy as well.

The biggest risk group of patients is really those with solid organ transplants and allergenic stem cell transplants. These patients are at very significant risk for acute organ rejection, which will be obviously a terrible outcome, secondary to immunotherapy.

And then finally the last group of patients we're quite cautious with are those who have quite poor performance status to start with. We tend not to give these drugs in patients that have an ECOG performance status of more than 2 because they just don't tolerate the toxicities very well.

You've talked about how no organ is sort of safe from immune-related adverse events, so obviously these require quite a lot of monitoring, and if something did go wrong then you would need a multidisciplinary approach. Do you want to talk a little bit about that and maybe what you might have seen in practice about how these sorts of things are managed and monitored?

Immune-related toxicities can actually be managed relatively effectively if caught early, which is why whenever we're starting a patient on these treatments we have a very frank discussion that if they were to develop any evidence of toxicity, whether that's diarrheoa or shortness of breath, they have a very low threshold for coming and seeking medical attention, because, like I say, if caught early these effects can be very, very well managed with usually just a short course of oral steroids, usually prednisone, and the omission of just one dose of immunotherapy with a plan to restart when these symptoms have resolved.

So there should be very low threshold for sending these patients into hospital and should always be making sure that the overseeing medical oncologist is aware that they've had this complication.

Luke, that's all the time we have for today. It's been a pleasure having a chat with you and thanks again for your time.

Not at all. It's been a pleasure. Thank you.

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The views of the host and the guests on the podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Jo Cheah, thanks for listening and I'll catch you next time.