Cool Science – DrAlice.blog

What is CAR-T therapy and why did NICE recommend against it?

You might have seen in the news today that NICE has denied patients access to a ‘pioneering’, ‘breakthrough’, ‘revolutionary’ treatment.

But what actually is this treatment?

CAR-T

CAR-T therapy is a type of immunotherapy that takes advantage of the cell killing capabilities of cytotoxic T cells. This particular type of T cell is an important part of the human immune system which for many years, researchers have hoped might be useful in treating cancer.

Cytotoxic T cells surround a cancer cell (taken from NIH)

The problem is, cancer cells are derived from your own cells so your immune system has no reason to target them for destruction. That’s where CAR-T therapy comes in. In CAR-T therapy, the T cells of the patient are taken from the blood and genetically modified so they express a chimeric antigen receptor (CAR). A CAR is basically a signalling molecule on the surface of the T cells that allow them to recognise cancer cells as worthy of destruction. These genetically modified T cells are then put back into the patient’s blood to target and kill cancer cells.

Because we know that different types of cancer typically have different types of signalling molecule on their surface, we can then use different types of CARs to help draw the cell killing T cells to the cancer cells. For example – nearly all types of B cell acute lymphoblastic leukaemia (ALL) have a protein called CD19 on the surface of cells so researchers have been working on CARs that specifically target cells which have CD19 on them.

B cell lymphoma cell is recognised by a T cell which has a CAR protein expressed on it — Modified from here.

Yescarta

The specific therapy that NICE has reported on this week is one called Yescarta from a company called Kite Pharma. Yescarta consists of taking T cells from the patient then using a system hijacked from retroviruses to genetically modify the cells. The genetically modified cells are then reintroduced to the patient in a single dose.

Clinical Trials of Yescarta have been initially promising. A phase II single-arm trial found that of 101 patients treated with Yescarta, 54% had a complete response and 52% survived over 18 months. All of these patients had refractory large B-cell lymphoma – that means they had a type of blood cancer that had already failed treatment and the patients had an average expected life expectancy of 3-4 months. While the trial showed that all patients had significant adverse events related to Yescarta, only 3% of patients died from the treatment itself.

Yescarta logo

Based largely on this trial the FDA approved Yescarta for certain types of lymphoma late last year and the European Commission granted Marketing Authorisation for the treatment this month.

Why not recommend it?

But NICE had some concerns. Firstly, they were concerned that the clinical trials for Yescarta, while promising, were insufficient to allow recommendation of the drug. While this particular type of lymphoma doesn’t have a standard therapy, yet, most patients are treated with scavenger chemotherapy and the Yescarta clinical trials haven’t proven that Yescarta is better than scavenger chemotherapy. The two therapies haven’t been compared side by side. This is quite a significant concern because, without side by side comparison, we can’t be sure that diverting patients from one treatment type to the other is actually beneficial for the health and life expectancy of those patients.

NICE aren’t saying no to Yescarta, they’re saying “not yet”.

The second concern NICE has is that the treatment is currently very expensive. The cost to the UK has not been made available, but in the US the treatment can cost $373,000 per patient. And this is something that NICE has to weigh up in its cost-benefit analysis. So far, Yescarta has been shown to prolong life by approximately 14 months in around 50% of patients. Is it justifiable to divert so many funds to a treatment that only works 50% of the time and we can only say extends life by a year (so far)?

A woman standing at a laboratory bench facing away from the camera and wearing a lab coat

The company that makes Kite Pharma was bought by Gilead Sciences last year, just two months before Yescarta was approved by the FDA. Last year Gilead Sciences had a revenue of $30.4 billion and a free cash flow of $15.9 billion. Gilead Sciences spent $12 billion in order to acquire Kite Pharma and its marketable therapy Yescarta. NICE perhaps has reason to be cautious.

Any other concerns?

If Yescarta were approved for the use in the UK, it would be the first of its type to be approved. There are potential concerns we need to consider when introducing both genetically modified cells into patients and playing around with the immune system in patients. In his article for McGill, Jonathan Jarry pointed out that “Autoimmunity is when our immune system improperly responds to something that belongs to us” and in the case of Yescarta we’re actively training the T cells to recognise cancer cells derived from our own cells. In fact CD19 isn’t just expressed on cancerous B cells, it’s found on all B cells – even the healthy ones. In the case of terminal cancer this might be a price worth paying but it has to be taken into consideration. Sudden activation of T cells in the body is such a strong response that patients can get very sick and even die from a condition called cytotoxic release syndrome.

We must also consider the reproducibility of the initially promising clinical trials. There is evidence that when repeated, less than 50% of clinical trial results are reproducible and many negative clinical trials go entirely unpublished which means a high likelihood of false positives, it seems prudent to take care when making decisions based on single clinical trials.

Conclusion

NICE - national institute for health and clinical excellence logo

While many patients were hoping for the approval of Yescarta by NICE, the limitations have proved too high at this stage. I don’t think this decision should be used to criticise NICE or the NHS, rather to encourage further research using reliable controls and a focus on bringing down the prices of promising new treatments. It also highlights an example where the novelty of new treatments can overtake scientific sense and lead to approving treatments which might currently be lacking sufficient clinical evidence supporting their use.

Meanwhile, the NHS will not withdraw funding for any patients already undergoing Yescarta therapy and will reconsider their decision given further research or reduced costs.

Cool science: Kick and Kill to cure HIV – an update.

A little while ago I wrote about an exciting new potential for HIV treatment. The cool idea was looking to solve a problem we haven’t yet figured out how to solve when it comes to treating HIV infection. You see, HIV is particularly tricky to treat because it forms what we call latent viral reservoirs. These are a group of cells that are infected with the virus but within which the virus isn’t ‘active’.

Antiretroviral drugs are really great, but they only target ‘active’ virus which means these reservoirs are essentially hidden away and protected. This is why people living with HIV need to stay on treatment for their entire lives.

So, researchers came up with a great idea – what if they could ‘kick’ the virus in the reservoirs into action and then ‘kill’ the now active virus using standard therapy. This scientific basis behind this ‘kick and kill’ approach made researchers think that this might hold the key to curing HIV and allowing people living with HIV to eventually come off their medication. Early studies were really promising and there was good evidence that this might be a useful approach to trial in patients.

So what happened next?

RIVER

The Research In Viral Eradication of HIV Reservoirs (or RIVER) study began in 2015 and concluded this year. This study was a randomised control trial (RCT) where 60 people recently diagnosed with HIV in trial centres across London and Brighton were split into two groups. One group received standard therapy – antiretroviral therapy (ART) only – this group acted as a ‘control’ group that could be used to compare the test group against. The test group were given a test therapy which consisted of four steps:

Patients were treated with standard ART until the ‘active’ virus was undetectable in the blood
Patients were then given a vaccine which would train or ‘prime’ the immune system to recognise the HIV virus
Patients were treated with Vorinostat which would ‘activate’ the inactive virus in the reservoir cells – this step is the ‘kick’ part of the process
The ‘primed’ immune system would then be able to ‘kill’ the newly activated virus

A four step diagram outlining the four steps included in the RIVER study - Step 1, ART is used to make sure HIV is undetectable. Step 2, two vaccines train the immune system to recognise cells which will be activated. Step 3, Vorinostat is used to wake the sleeping cells. Step 4, the immune system boosted by the vaccine attacks and kills the newly activated cells

What did RIVER find?

The results were surprising and unexpected. RIVER found that there was no significant difference in the size of the latent HIV reservoir between standard treatment (control) and ‘kick and kill’ treated (test) patients. It looked like ‘kick and kill’ was no better than standard therapy.

Even more surprisingly, each of the components –the standard antiretroviral medication, the vaccine which primed the immune cells and the Vorinostat which ‘kicked’ the inactive virus into action – all worked exactly as they should. But combining the multiple components wasn’t any better than ART alone.

Chief Investigator on this study, Prof. Sarah Fidler of Imperial College London said “In the RIVER study, we found that all the separate parts of the kick and kill approach worked as expected and were safe. The vaccine worked on the immune system, the kick drug behaved as we expected it to, and the ART worked in suppressing viral load in the body, but the study has shown that this particular set of treatments together didn’t add up to a potential cure for HIV, based on what we’ve seen so far.”

Does this mean we should drop the kick and kill approach?

Well, no, not really. Because this was just one iteration of the kick and kill approach using a combination of one type of medication and two types of vaccine. Researchers on the RIVER study aren’t really sure why it didn’t work as planned but until we understand the answer to that question it might still be a useful avenue for research.

a drawing of an HIV viral particle surrounded by blood cells and coloured with dark purple and brighter patches of fushia

The co-principal investigator and scientific lead from the University of Oxford, Prof. John Frater says “It is possible that the combinations of drugs we used weren’t quite right, but for this first study we didn’t want to compromise on safety by using stronger agents that might work better but could cause toxicity to the participants. It is possible that vorinostat was not quite potent enough to wake up as much HIV as was needed for the newly trained immune system to recognise. Equally, it is possible that a different sort of immune response to the one we induced is needed to target the HIV reservoir. All of these possibilities need to be teased out and considered to guide our next move in searching for an HIV cure.”

So what next? Collaborative research.

This RCT is an important step in investigating the possibility of curing HIV infection. Professor Abdel Babiker of the MRC Clinical Trials Unit at UCL, said “Although the results are disappointing, they are unambiguous because of the randomisation and completeness of follow up assessments. Because ART is so effective at reducing viral load, without the randomised control group of participants taking ART alone to compare against, we couldn’t have been so confident in knowing whether the kick and kill drugs had made any impact. It’s important that future HIV cure trials follow this approach and compare their outcomes to an ART-only group.”

A woman standing at a laboratory bench facing away from the camera and wearing a lab coat

Scientific experimentation using RCTs allows us to be confident in the findings – even if those findings are not as promising as we hoped they would be.

This particular trial was part of a UK collaboration group called CHERUB but there are collaborative groups like this all over the world. The value of collaboration allows experts from different backgrounds, with different expertise to come together and conduct research with wide ranges of participants. The importance of participant engagement in particular was praised by Prof. Fidler who said “They are not just volunteers, they are active advocates for support and they push us to go further all the time. They are helping to define where this research can go next and they are the real pioneers of new treatments.”

Find out more about this trial here and here.

Cool science: using Zika virus to treat cancer?

Throughout the last two years there has been a great deal of news on the Zika virus – a virus spread by mosquitoes which was first identified in 1947 in Uganda. In a normal healthy adult Zika fever causes relatively mild symptoms or even none at all however the 2015-2016 Zika epidemic gave rise to widespread concern due to its propensity to cause microcephaly and brain defects in babies infected with the virus during development. The epidemic was declared over in late 2016 although there are still travel warnings to certain areas where the mosquitoes known to carry the virus are prevalent.

But research into this particular virus highlighted an interesting trait that we might be able to take advantage of – Zika has a preference for stem cells.

Zika and stem cells

The reason Zika virus is particularly dangerous in developing babies is that the virus causes damage in stem cells in the brain. A stem cell is a cell that isn’t yet programmed. They’re really important in development because when you create a baby you start with one sperm cell, one egg cell and these cells needs to combine, proliferate and then differentiate into all the different types of cell within the human body. Stem cells are unique cells that can be programmed or ‘differentiated’ into all sorts of different types of cells. Once a stem cell has differentiated it can’t turn back into a stem cell – a differentiated cell is committed to only ever being that cell type. The adult body has very, very few undifferentiated cells but a developing foetus has plenty. This explains the risk of Zika infection during pregnancy as Zika has been shown to target neural progenitor cells – a type of undifferentiated cell in the brain – that might lead to the microcephaly seen in babies infected with the virus during their development.

480px-Zika-chain-colored — Crystal structure of the Zika virus

Zika and brain cancer

Cancer stem cells are quite a complicated thing that I’m not going to try and do justice in this post because it’s a topic that deserves its own post. Scientists believe that some cancers do have associated cancer stem cells. How exactly cancer stem cells might contribute to cancer progression is far from fully understood. However, we do believe that the presence of cancer stem cells might contribute to cancer therapy relapse. This is particularly concerning in glioblastoma – an aggressive form of brain cancer, which has poor survival rates despite our best efforts. Without treatment, median survival is around 3 months from diagnosis. With treatment we are able to extend that survival to 12-15 months however the cancer usually recurs. Scientists believe this recurrence is all down to the presence of cancer stem cells.

The study

So here’s the clever part. Cancer researchers know we have a problem in treating glioblastoma. They also realised that Zika virus is a relatively mild virus, which attacks stem cells. The adult brain doesn’t really have stem cells – unless the adult has glioblastoma. Cancer stem cells in the brain lead to cancer relapse; Zika attacks brain stem cells. Maybe we can make use of these two pieces of information.

So, scientists did some experiments. Firstly, they took some glioblastoma cells from patient tumours and they grew them in a dish in the lab. Then they infected them with Zika virus. They looked at either glioblastoma differentiated cells or glioblastoma stem cells. And they looked at the infection rate. Over 48 hours, over 60% of the stem cells were infected and this increased over time as the virus spread. The differentiated cells were infected too but not as much. What was especially interesting was that the stem cells infected with the virus had severely reduced ability to multiply and they had an increase in cell death. This was specific to only the stem cells and didn’t affect the differentiated cells. The virus kills cancer stem cells and prevents them from spreading.

Next the scientists took some patient tissue samples – this allowed them to look at a whole mixture of cells in a slightly more normal context without having to infect patients. They infected the tissue samples with Zika and saw that cancer samples were infected successfully and the virus only hit the stem cells and not the other cell types in the sample. They also looked at some brain samples from epilepsy patients and the virus didn’t infect them showing that the virus really is specific for stem cells!

jem.20171093 — Glioblastoma tissue sample (from the paper)

Finally, they used the virus to treat mouse models of glioblastoma. They took mice with glioblastoma tumours in the brain and infected them with the virus. They saw that the tumours were much smaller and the mouse had improved survival when they were infected with the virus compared to control treated mice. They went on to show that they got an even better effect when combined with other glioblastoma treatments.

Benefits

Current treatments have two problems when it comes to glioblastoma. Firstly, the cancer stem cells make recurrence almost inevitable. This could drastically improve average survival times. Secondly, all brain cancer treatments have to be able to cross the blood-brain barrier in order to get through to the cancer cells. The blood brain barrier is an important way to keep things out of the brain where they might cause damage but it also serves as a way to keep brain tumours trapped in and harder to treat. Zika is great at crossing the blood-brain barrier.

What next?

We’re still such a long way from this being a useful patient treatment. In order to use this as a treatment we need to modify the virus in such a way that it will not spread from person to person and it will not cause the patient any harm. Currently virus work is always done in very specialised laboratories with expert training on how to prevent spread and with many, many precautions. If it were to be used as a therapy we’d need lots and lots of precautions to make sure it were safe. So far this has only been done in lab grown cells (albeit ones taken from patients mouse models of cancer. But it’s incredibly interesting research and a great example of how cancer research is so quick to develop and understand how we can take advantage of what we know about the disease and use that to treat it.

Please let me know in the comments if you’d like to see a post on any of the topics from this post – Zika virus, glioblastoma, stem cells?

If you found this interesting, please share it with three other people who might find it interesting too! Sharing cool cancer research gives us all a little more hope!

Image credit for the crystal structure of Zika: By Manuel Almagro Rivas – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47941048

Cool Science: taking advantage of cancer cell biology for cancer treatment

One of the big problems when it comes to treating cancer using drugs is that these drugs flood the patient’s body and cause detrimental side effects when they reach areas other than the malignant tumour. Cancer cells are derived from our own healthy cells – they’re hard to target specifically without also hitting our healthy cells. A lot of research goes into trying to get around this problem. I came across a particularly interesting study that I thought I’d share here.

Earlier this year Sofie Snipstad et al. published a paper in Ultrasound in Medicine & Biology titled “Ultrasound improves the delivery and therapeutic effect of nanoparticle-stabilized microbubbles in breast cancer xenografts”. This paper was particularly cool because of the rationale behind it. Nanoparticle delivery of drugs is something scientists have been working on for a little while. The premise is that you take your drug and you wrap it up inside a small protective bubble allowing the drug to travel to a specific site before it is released. Due to a quirk of cancer biology, this is particularly great as a cancer therapy. When tumours grow, they start to form their very own blood supply – only the blood vessels that they grow are more leaky than normal blood vessels. They allow slightly larger molecules to pass through from the blood vessel and into the surrounding tumour. This means we can use nanoparticles to deliver cancer drugs specifically into tumour sites by allowing the particles to travel through these leaky blood vessels. But then we hit another problem – if the tumour blood supply doesn’t reach the very depths of the tumour then the particles are too big to get all the way through. You can treat the edges but not the very centre of the tumour. So, this paper worked on a special combination – they took a bunch of nanoparticles containing chemotherapy and they bundled them up together into microbubbles that can travel around the blood system easily and safely until they reach the tumour site. Then, the researchers used a focused shot of ultrasound to break up the bubbles and release the nanoparticles. This also served to allow gentle tissue massage by the ultrasound to allow the nanoparticles to distribute further throughout the tumour. Once in the tumour, the cancer cells start to take up the nanoparticles and inside the cell the drug is released and can kill the cancer cell from the inside.

Image: figure from the paper

Any microbubbles that weren’t in the tumour site and therefore not exposed to the focused ultrasound could be easily cleared from the body without releasing the drug which means the only cells targeted by the therapy are the cancer cells. This means we can hit the cancer cells with a higher, more toxic dose because the healthy cells are not going to be hit with the same dose.

The researchers in this paper were testing the optimal way of doing this in mice suffering with triple negative breast cancer – one of the more aggressive forms of the disease – with positive results. The mouse tumours took up the drug 2.3x better and there was no tissue damage identified. All of the tumours either regressed or else the mice went into complete remission. The authors described this as a “promising proof-of-concept study”.