S2 E8 CAR-T cell therapy

In this episode, RCPA President Dr Lawrie Bott and internationally recognised haematologist Professor Miles Prince discuss CAR-T cell therapy, a new complex and specialist treatment that is being used to cure certain types of blood cancers. 

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00:00:00:22 - 00:00:17:00

[Voiceover]

Welcome to the Pathologists Cut podcast. This RCPA podcast explores the broad medical specialty of pathology and the critical role pathologists play in medicine and health care.

00:00:17:02 - 00:00:51:22

[Dr Lawrie Bott]

Hello and welcome to the RCPA Pathologists Cut Podcast Series. Today we are talking to Professor Miles Prince about CAR T-cell therapy, a new complex and specialist treatment which is being used to cure certain types of blood cancers. Earlier this year the TGA approved CAR T-cell therapy to treat multiple myeloma. Following a campaign from Professor Prince to make the treatment which he refers to as the holy grail of cancer cures available to all Australians.

00:00:51:24 - 00:01:19:14

[Dr Lawrie Bott]

Professor Prince is an internationally recognised haematologist and Professor at both Melbourne and Monash Universities. He is engaged in research into stem cells and the mechanisms of the immune system's control of blood and cancer growth. This research focuses on targeted treatments for blood diseases, including CAR T-cell therapy. Thanks for joining us today, Miles.

00:01:19:16 - 00:01:25:03

[Prof Miles Prince]

Thanks very much, Lawrie. Looking forward to the chat.

00:01:25:03 - 00:01:45:10

[Dr Lawrie Bott]

Miles, CAR T-cell therapy seems an extraordinary advance in the treatment of multiple myeloma and cancers in general. It's been said that many cancers through therapies such as this will be curable within a matter of years. Perhaps you can start by explaining what CAR T-cell therapy is.

00:01:45:14 - 00:02:35:07

[Prof Miles Prince]

So that stands for chimeric antigen receptor T cells. And fundamentally what happens is that it is modifying the patient's own T cells to be specifically directed towards the tumour of choice. So, practically speaking, patients have their cells apheresed, like standard apheresis, T cells are purified, usually there is predominantly CD4, CD8 population. The cells are then mixed in a cocktail of cytokines which activate the T cells, and during that process the retrovirally transduced with an empty vector that contains the gene for the chimeric receptor.

00:02:35:09 - 00:03:04:18

[Prof Miles Prince]

So, for example, it can be a lentivirus that contains the gene for CD19 or in the case of myeloma, BCMA and that gene is then incorporated. The culture process varies from seven to 12 days, and that's important because the T cells that are cultured during that time need to have a phenotype that is long living and that's something we can talk about.

00:03:04:23 - 00:03:39:12

[Prof Miles Prince]

But it's actually quite an interesting technique because you can modify the conditions to make different type of activity cells, ones that are cytotoxic and immediate killers or ones that have more of a central memory phenotype that hang around for a while and that's one of the areas of interest. And so after culturing those T cells, they then simply centrifuged and put in a bag and then re-infused into the patient like a transfusion, the T cells then proliferate and will go and bind to the target.

00:03:39:16 - 00:04:10:21

[Prof Miles Prince]

So, for example, in lymphoma the CAR-T cells will be directed to the lymphoma cells. As soon as the CAR-T cells bind on, you get activation of those T cells. So what happens is that the actual receptor has three components. That's the gene that's inserted, it's got the target. So for example, that the lymphoma, it might be CD19 lymphoma, myeloma, it might be BCMA.

00:04:10:23 - 00:04:40:03

[Prof Miles Prince]

Then, there's a transmembrane domain which has activation molecules which will activate the T cell. So, for example, it might be BB1 or CD28, and that will then stimulate that T cell. So you'll get engagement through the receptor, activation of the T cells, the T cells will then proliferate and then produce cytokines and be directly cytotoxic. And so you'll get killing of the cells.

00:04:40:05 - 00:05:05:12

[Prof Miles Prince]

The beauty about CAR-T cells is twofold. One, it's, you know, it's called the live drug because the T cells will not only bind on to the lymphoma target lymphocyte, it'll then disengage and then go and bind onto another. And we wrote a paper a few years ago called ‘Serial Killers’ because they can kill, you know, eight to 14 specific cells and you can get rapid tumour lysis.

00:05:05:14 - 00:05:28:09

[Prof Miles Prince]

The second thing is, is that the T cells have a memory. So the T cells will stick around and we can measure them and they can last for a few weeks or a few months or even years and permanently. So if there is regrowth of the tumour, then just like you've vaccinated the patient, you'll get regrowth and the T cells can then kill.

00:05:28:11 - 00:05:59:17

[Prof Miles Prince]

And that's an area of real interest because we want to optimise that balance between good cytotoxicity as well as long-term persistence of the cells, which makes them really exciting because it can basically prevent the tumour for the rest of the life. So fascinating technology and to be honest, it is constantly developing. There is just so many papers looking at how we might modify all those different steps to optimise the T cells.

00:05:59:19 - 00:06:09:16

[Dr Lawrie Bott]

Extraordinary. The targeted nature of it is just amazing. Who will benefit from this type of treatment, Miles?

00:06:09:18 - 00:06:45:02

[Prof Miles Prince]

Well, it's already approved. The first approval was for B acute lymphoblastic leukaemia. And for patients who are paediatric young adults, that's for patients who have failed induction treatment and usually allogeneic transplant. In some situations, it can actually be used for a bridge to allogeneic transplant and it's potentially curative. There is a cure rate that's variable depending on the study in the group between 30 and 70%.

00:06:45:04 - 00:07:15:11

[Prof Miles Prince]

The second major indication was in diffuse large B-cell lymphoma for patients who either were transplant ineligible or patients who had relapsed after bone marrow transplant. And that's currently been approved in Australia. There's two different companies that produce the T cells. The third current indication that's been approved and we're waiting for the final implementation, which gets down to how do we fund all of this.

00:07:15:11 - 00:07:50:02

[Prof Miles Prince]

But mantle cell lymphoma. So that's been approved in Australia but not being used commercially yet, one would hope. And all of those targets are CD19. The big breakthrough has been in myeloma where the CAR T is targeted against anti BCMA B-cell maturation antigen, which is localised on mature plasma cells. And so that's just been approved with a big nudge in the ribs of the Health Minister to get the TGA to finally approve that.

00:07:50:04 - 00:08:18:01

[Prof Miles Prince]

But it's yet to get the final approval through PPC slash through MSAC. It's a little bit unusual, that funding model. The next cabs off the rank ultimately are going to be other solid tumours, but there are problems with solid tumours and they may well be micro-environmental where there's lots of studies but solid tumours are proving to be a bit more difficult than initially anticipated.

00:08:18:03 - 00:08:30:09

[Prof Miles Prince]

Perhaps we could talk a little bit more about that later. One of my questions was in terms of the infusion, is the infusion repeated or is it just a one-off therapy?

00:08:30:11 - 00:09:17:24

[Prof Miles Prince]

With the standard CAT-T cells, so the CAR-Ts that are predominantly CD4, CD8 population and it's a one off and long-term survival. But there are other types of lymphocytes that are being looked at and NK cells which are not typically long surviving. And so there are some strategies of using multiple infusions. The other interesting area is using allogeneic CAR-Ts. So a more off-the-shelf strategy, that's a big area and it's very tempting because the big problem we have with CAR-Ts is that as I've explained to you, it's often in a relapse setting for lymphoma and getting the patients to get bulk reduction, being able to collect their T cells, grow them in

00:09:17:24 - 00:09:48:09

[Prof Miles Prince]

that period of time, and for the disease to be in control for what works out to be a few weeks can be challenging. And so the idea of having a bank of T cells that can be potentially matched with a whole lot of people and just be pulled off the shelf is really exciting. And there's a number of companies, lots of trials, and that may broaden the availability of it for patients, but there's nothing near a standard approach yet.

00:09:48:11 - 00:09:59:01

[Dr Lawrie Bott]

So you've been working on genomics and personalised medicine for some time now. Overall, where do you think we stand today in terms of treatment for blood cancers?

00:09:59:03 - 00:10:22:05

[Prof Miles Prince]

Yeah, look, I think genomics, you know, for this audience, they'll know that the key thing for genomics really has been around getting the right diagnosis. I mean, I use a genomic panel for myeloproliferative diseases literally every day trying to define, you know, myelofibrosis, etc. We use it for AML all the time to subtype. So it is splitting up and directing our treatment.

00:10:22:05 - 00:11:00:00

[Prof Miles Prince]

So you see KIT mutations, etc., NBN. We're using it all the time diagnostically. The next step really is to sort of say, is there a targeted therapy? And, no question, that targeted therapies are developing. So we have got IDH inhibitors, for example, which are available for MDS and AML. There are C-KIT inhibitors for mast cell diseases. So what we're going to see, I think over the years is going to be a progressive increase in the repertoire of potentially targeted therapies for myeloid malignancies, lymphoid malignancy.

00:11:00:00 - 00:11:24:01

[Prof Miles Prince]

So, for example, EZH2 is a common mutation seen in lymphoma. There is now EZH2 inhibitors. So I think we're just going to see this one used every day for diagnostics and two for target choosing and specific targeted treatments for patients with across the board haematologic malignancies.

00:11:24:03 - 00:11:39:06

[Dr Lawrie Bott]

You mentioned the TGA has approved CAR-T therapy for multiple myeloma. It is the first time in Australia that a treatment has been approved for use against the common cancer. Can you explain what this TGA approval means?

00:11:39:08 - 00:12:06:24

[Prof Miles Prince]

Yeah, so look, the first ones were for lymphoma was very much the situation of patients with relapsed disease. So about 2000 patients per year are diagnosed with diffuse large B-cell and we cure about 70% of them. For the patients who are eligible in terms of age, it makes it about 300 a year potentially if it catches on. There are issues of, you know, getting the patients to CAR-T cell therapy.

00:12:06:24 - 00:12:33:12

[Prof Miles Prince]

So it's relatively small if you spread that number around Australia and it's also needs to be done pretty quickly. So myeloma is a different paradigm because from day 1 the patients know that they've got an incurable disease. So in myeloma it's been approved by the TGA for after third line therapy. So that means we can start looking at providing it, but it's not reimbursed.

00:12:33:12 - 00:13:01:24

[Prof Miles Prince]

And the big problem here is that it's got to be approved by the PBAC as well as MSAC, because the PBAC pay for the drug, which is about well, we don't know the exact number, but it's about $400,000 to $600,000 per patient and that's got to be paid to the drug company to produce it. And then the patients actually have to be looked after in the hospital and that means the States have to pay for that, which means MSAC kicks in.

00:13:02:01 - 00:13:34:03

[Prof Miles Prince]

And so this is the clinical football in terms of who's been paying for it. And that's a bit where we're stuck at the moment. And the discussion I've been having and a number of the groups, including HSANZ and Myeloma Scientific Advisory Group, have been arguing with the government about, you know, had they been making rational decisions about the funding because last year in August MSAC rejected it really on very inappropriate illogical reasons, reasoning that they did not use for the other indications.

00:13:34:05 - 00:14:02:09

[Prof Miles Prince]

And it's because it's so expensive. At the current indication, it is about 270 patients per year. But if it moves closer and closer to diagnosis, then you starting to look at, you know, 2700 patients a year are diagnosed with myeloma. So if it became second line, not fifth line, the numbers go up substantially. Now, you know, the costs will come down as everything does.

00:14:02:09 - 00:14:29:07

[Prof Miles Prince]

But, at the moment, it looks like a very expensive strategy. The problem is, is that the government's not even preparing for it. They're not even thinking about how they fund these things, how they can optimise it, how they can engage with pharma to perhaps even reduce the prices. So I'm fighting a bit of a political battle to try and get people to start recognising what I call the tsunami of immunotherapies that's coming over the horizon.

00:14:29:12 - 00:14:39:15

[Prof Miles Prince]

And for us to be at least prepared for this from a delivery point of view: people have to be trained as well as an economic point of view.

00:14:39:17 - 00:15:01:24

[Dr Lawrie Bott]

You mentioned that, in terms of funding, we're at the start of an innovation and of course it's expensive. So the expectation presumably is that, as you mentioned, it will go down in cost. Is the government considering this in their funding proposals?

00:15:02:01 - 00:15:26:05

[Prof Miles Prince]

No, not really. And I think the other issue is, is that there's other technologies called bispecific antibodies, which is, you know, dual bonding antibodies, which are given as a drug and they're going to compete with CAR-Ts. They're very effective. They have different toxicity profiles etc, but the whole landscape of where it's all going to fit in competing technologies, reducing prices.

00:15:26:07 - 00:15:51:07

[Prof Miles Prince]

And this is really what I'm arguing for, that we have something like a thinktank that can feed into the government and start looking at these things. For example, we've had three drugs for myeloma approved in the United States, three bispecific antibodies approved. And so we know they're going to be on the horizon in two years. But Australia's regulatory authorities, they don't get ready for it.

00:15:51:09 - 00:15:55:24

[Prof Miles Prince]

And so it then delays all of this.

00:15:56:01 - 00:16:06:18

Dr Lawrie Bott

Yes, I guess in general terms, it's this disconnect between the political cycle and I guess the medical development cycle.

00:16:06:20 - 00:16:20:17

Prof Miles Prince

Yeah, and look, you know, the pharmaceutical companies who produce these drugs and they do cost the health system because people have to be trained and the process is quite boutique and they should be contributing to the cost of those things.

00:16:20:19 - 00:16:29:05

[Dr Lawrie Bott]

Yes. So, Miles, I was just wondering about side effects. We haven't talked about this. Are there side effects to these treatments?

00:16:29:07 - 00:16:56:19

[Prof Miles Prince]

There’s two major things. One is cytotoxicity. So the cytokine release syndrome. So if these cells proliferate quickly, they produce large amount of cytokines, particularly interleukin-6, and you can get a real high fevers, septic-type episode. The anti IL-6 six antibody with steroids works extremely well. And so we got better and better at managing those toxicities.

00:16:56:19 - 00:17:27:17

[Prof Miles Prince]

But then there's also neurotoxicities that can occur, which are a little bit more complicated, but again, are generally manageable. But they actually may be more of a problem as we use these treatments perhaps in older people or perhaps earlier when the immune system is really very active early in disease. And so neurotoxicity can take the shape of anything from tremor to cognitive problems, pseudo-strokes.

00:17:27:19 - 00:17:53:18

[Prof Miles Prince]

And then there's a sort of degenerative neurotoxicity that we seeing, quite rare, and a lot of these are very manageable, but quite rare, and that may be more of an issue. I don't think we've really nailed that more chronic neurotoxicity-like sort of Parkinsonian-type of effects. So I don't want to overemphasise them. But like any developing technology, things can take us from the side and unexpected.

00:17:53:23 - 00:18:22:03

[Prof Miles Prince]

The other is particularly in lymphoma and myeloma, where we're targeting B cells, we get hypogammaglobulinemia. So patients often require immunoglobulin replacement. And infections. I think not only with this, but with the biospecifics, where we're knocking off large amounts of normal B cells in various compartments, blood, marrow, spleen, lymph glands, we're going to see issues with infection.

00:18:22:05 - 00:18:41:12

[Prof Miles Prince]

And I think, you know, from the pathology perspective, we're creating an industry here of immune suppression. And it's not just that things that we've talked about, but all of the antibodies and all of the new immune therapies we have to be prepared for the infection problems that we may well face.

00:18:41:14 - 00:19:00:19

[Dr Lawrie Bott]

Yes, thank you. And of course, there's side effects with all oncology treatments. So an exciting thought I had in terms of other cancers. I mean, can this technology be applied to other cancers, particularly solid cancers, sometime in the future?

00:19:00:21 - 00:19:28:01

[Prof Miles Prince]

Well, I think it's anything where a T cell is important. And so, you know, we've learned from the checkpoint inhibitors that there's a lot of cancers that are very dependent on the T cells. We're using checkpoint inhibitors for bladder cancer, lung cancer, etc. So there's a lot of trials that are being done. The most predominant ones have been in lung cancer, pancreatic cancer, ovarian cancer looks very interesting.

00:19:28:05 - 00:20:04:19

[Prof Miles Prince]

I personally think that that's an interesting one because, you know, advanced ovarian cancer, often peritoneal, and they can be targeted. So the problem has been that getting these cells into a what is a relatively hostile microenvironment as opposed to the marrow components, which are a bit more accepting of T cells. They’re used to having T cells floating around in there. 

00:20:04:19 - 00:20:22:21

[Prof Miles Prince]

Other conditions, rheumatological conditions targeting T cells or even some viral conditions targeting T cells, infections conditions, diseases like diabetes have been under active investigation where the T cells are out of control. T cells seem to be important, so it's going to go beyond just cancer.

00:20:22:23 - 00:20:30:08

[Dr Lawrie Bott]

Where is it being worked on in the world? There must be other centres working on this therapy.

00:20:30:10 - 00:20:55:02

[Prof Miles Prince]

Yeah. Look, there was a nice publication last year looking at where all the trials are. And if you look at where all the trials are, they are actually in the US and China. There's a massive amount of research being done in China. But is predominantly US. There's obviously some in Europe. We're doing, you know, Australia is, is doing a number of really interesting preclinical work, particularly in some of the neurological conditions, CNS disease.

00:20:55:08 - 00:20:59:20

[Prof Miles Prince]

But the most of the clinical trials are coming out of the US.

00:20:59:22 - 00:21:12:13

[Dr Lawrie Bott]

So, you mentioned before the Australia being ready for the use of this technology, particularly with funding. Have you got any other comments about us being ready?

00:21:12:15 - 00:21:55:16

[Prof Miles Prince]

I think the problem is, is that the Departments of Health really don't understand what's happening on the horizon. And I think they need to be educated. So just like we have the Grattan Institute and the Lowy Institute, educating about financial issues, really educating the government, providing formats for which people can talk, debate, bring up the issues, we need to have something similar and there is currently a high technology assessment review and they've already commented that they need something that's horizon-gazing to look at all of these high technology treatments and they include even some of the enzyme replacement therapies, etc.

00:21:55:18 - 00:22:29:20

[Prof Miles Prince]

We were talking about genetic issues, the whole area, you know, of where there are gene deficiencies and they're all expensive. So, we need something horizon gazing. But, you know, my concern is if it's buried within the Departments of Health, then they are subject to deportation of funding, etc. We need something bigger and something that can really address all the issues which go across the departments, including industry, because Australia has a huge opportunity here to become to, you know, sovereignly produce.

00:22:30:01 - 00:22:57:06

[Prof Miles Prince]

That's one of my arguments is that we are very dependent on overseas production where we have to literally send the cells to somewhere overseas. And so we're fighting to have places like Peter Mac to do more production. But you know, we have a great immunology history here in Australia and you know, places like CSL are very capable of being production contributing to the capacity to produce.

00:22:57:06 - 00:23:27:13

[Prof Miles Prince]

So I think there's real opportunities and eventually this sort of treatment will become small scale. We'll have little incubator boxes in hospitals. We, you know, we've got a lab at Epworth where we've built specifically in anticipation for taking this sort of technology and for it not to be needing to be done in large clean rooms, but to be done in small incubators like, you know, pharmaceutical production, which is really where I see it going.

00:23:27:15 - 00:23:31:19

[Dr Lawrie Bott]

And as you said, it needs funding to get to that point.

00:23:31:21 - 00:23:37:01

[Prof Miles Prince]

It needs to be evaluated what it is and then work out the funding.

00:23:37:03 - 00:23:47:23

[Dr Lawrie Bott]

So, everything considered, it sounds like a very exciting time to be a haematologist. What would you say to someone who hasn't perhaps consider this as a career choice?

00:23:48:00 - 00:24:08:10

[Prof Miles Prince]

Well, I think, you know, the beauty about haematology is that note the balance between the clinical and the laboratory and then the research. And, as my daughters would say, it's a pretty awesome time to be haematologist because we are really striving forward at the cutting edge. So I think we're just going to cure more and more people.

00:24:08:10 - 00:24:36:01

[Prof Miles Prince]

We're going to be faced with more challenges. We've got a lot of translational research happening and it's certainly going to be a huge change in the next 20 years. So for any young person who's interested in looking after patients over a long period of time and managing them and being involved with both the clinical and the pathology side of things, haematology is fascinating.

00:24:36:03 - 00:24:56:05

[Dr Lawrie Bott]

Thanks, Miles, and thanks for talking with us today. CAR T-cell therapy is such an exciting technology and it's got extraordinary potential. I think anyone listening to this podcast would be able to see that. It's been wonderful to explore this therapy with you today. Thank you.

00:24:56:07 - 00:24:59:09

[Prof Miles Prince]

Thanks very much, Lawrie.

00:24:59:11 - 00:25:14:18

[Voiceover]

You have been listening to the Pathologists Cut podcast with RCPA President Dr Lawrie Bott. To learn more about pathology. Check us out on Facebook, Instagram and Twitter.