Seasoned Pharmaceutical Quality expert Lieve de Wolf (External Quality Manager CAR-T & Advanced Therapies at QbD Group), joined our inaugural annual Scilife Summit to answer everything you wanted to know about novel GTMPs and ATMPs, specifically CAR-T products, licenses & manufacturing, in a fruitful Ask Me Anything session.
Her comprehensive talk and Q&A session covered Quality issues around Advanced Therapy Medicinal Products (ATMPs), Gene Therapy Medicinal Products (GTMPs), and the CAR-T manufacturing process.
Below, the top 10 questions from the session with Lieve’s answers in her own words.
1. Are CAR-T products classified as GMO (Genetically Modified Organism) products? What are the complexities?
That's a very clear question. So as explained, you use cells so those are organisms and we will genetically modify them by the viral vector. So in fact, the definition of a GMO is completely fulfilled. So that's a yes. Then the complexities, that's more related to clinical studies and also a little bit of the European member states. So each member state will have its own rules of how you need to apply for a clinical trial and with a new directive of clinical trials and initiatives. There are also already some harmonizations for your clinical trial application, but that's not the case for the GMO application. So you will still need to do multiple applications in different countries. All countries request some specific regulations for those GMOs. That can make it a very long and also very extensive process to map out all those differences and to have your CAR-T product available in all the countries. So I think that's the main difficulty, to have those GMO licenses because that is not really harmonized. Some countries have mutual agreements, but it's not that clear yet.
2. What are CARs?
CAR stands for Chimeric Antigen Receptors. Chimeric because it uses the ability of a B-call and a T-cell. It uses the antigen recognition section of a B-cell so that it can target an antigen on a tumor, but then it also has the machinery of a T-cell to stimulate the T-cell to make those cytokines and to do the normal way of how a T-cell works. It's an antigen because it targets a cell, and then of course it's a receptor since it is at the outer surface of the cell.
3. What are the key disadvantages and advantages specific to CAR-T cells? Expansion strategies when you scale up from a reactor, for example, from batch size, about 10 liters to a batch size tenfold, a bigger, let's say 50 or hundred liters.
The question is for me not that clear because if you are talking really of the cell expansion of CAR-Ts, as mentioned during my slide deck, normally the expansion is done in a GREX and those GREX I think the maximum amount of working volume is between one liter and I think for a wave bioreactor, it's only five liters. Maybe the person is more focused on lentiviral vector production. There of course we use larger batch sizes. So there it's mainly common to use a 40 liter, 50-liter Bioreactor, but for CAR-T products, and also because T cells are very subtle, I don't think it's a good approach to upscale. I think it's better to have multiple because it's also an auto Locus product at this moment. You have multiple outscale production flows, so if you have one production line and you just copy it with 50, then you can produce CAR-T for 50 persons at the same time.
So I don't understand completely the question, but normally for CAR-T production, the expansion of CAR-T cells is not done in that batch size type.
4. You mentioned that the cells and tissues have to follow the specific guideline and the resulting ATMP corresponding legislation. Does this mean that different types of licenses will have to be applied for?
It depends on who you are. So, as a manufacturer, you need to have your GMP license. So there you will follow the ATMP regulation and GMP for ATMPs, but of course, you will need to acquire your cells. And that is done in hospital sites, cell collection banks, etc. So the hospital itself or the blood bank or tissue establishment, they have their own license to collect cells according to the tissue directives. The manufacturer needs to have a risk assessment and a strategy for how to audit and qualify those hospitals because, at this moment, a hospital is becoming a critical supplier.
So you acquired the cells of the hospital, then they are your supplier, but they will also treat the patient. So it's like that entire supply chain vein to vein, and now the hospitals, and that makes it also very difficult for both partners since hospitals don't work like a GMP facility. So then you need to find a Lean approach to audit them, but also they need to follow the tissue directives and they have their own license.
5. I suppose that for the cell part, you need to apply for a cell bank license or similar?
The cells themselves, are covered by the hospital. They have their licenses. Of course, you need to check that they have it and you can also see it. in that supply chain, the vein to vein, it's very important traceability. For traceability, we use donor identification numbers. And that's also mandatory. So in the European section, you will need to use the SEC-DI. So that's this defined code number code that will specify the hospital site. So then you know they are qualified and you can also check their license on a platform. And of course, you can screen hospitals and select them if they have the correct licenses.
6. Can we also use CAR-T therapies for solid tumor cancers?
Yeah, so that is currently in the pipeline. So there are lots of clinical trials regarding solid tumors, but why are they not ready already on the market? That's because it's very difficult. As I already mentioned, the CAR-T cell needs to target a receptor on the tumor. And now the current CAR-T types are used to treat Leukaemia etc, so they target like CD90 and BCMA receptors. But for solid tumors, it's very difficult to find a receptor - the antigen where the receptor needs to bind. So it's very difficult to target the tumor cells because they're a microenvironment. So tumors have a microenvironment and the engineered CAR-T cell cannot reach the tumor. So they are trying to develop new mechanisms like using different types of CARs with maybe two receptors engineered, or infusing different CAR-T products in the same bag. But it's still ongoing and the trials that are now being tested, I'm not up to date with all the trials, but a lot of times the efficacy or the activity is very low and it's very disappointing. There are also more safety risks. You have more challenges to overcome.
7. What is the difference between cell and gene therapy medicinal products?
I can better state it with an example. So, the main example of cell therapy is like Provenge, that's against prostate cancer. For CAR-T, we use a T-cell and for Provenge, they use the antigen-presenting cell, so also cells from our human body. But the main difference is, they collect the cell the same way as CAR-T and they also inject a protein. So the antigen-presenting cell will recognize that protein and will take it up like it's the normal function. So you create an activated cell, but you just use the same machinery. So it's not that you engineer or change something about the antigen-presenting cell, you just let it work how it's supposed to work. And then you inject that antigen-presenting cell back into the body. And that's the main difference.
So, in both cases you use cells, but it's not that you engineer it. You don't use a DNA or an RNA vector. You use properties of the cell and then depending on the disease, you will inject it into another part of the body and then state that it is a cell-based therapy.
From the moment you use those engineered cells, then it's gene therapy. The main difference is the mode of action and how it is made. I agree classification is very difficult. Also, the EMEA guidelines state that there is a frequently asked question or guideline regarding classification initiatives from the CAT (Committee for Advanced Therapies) to classify products in early stages. So I think everyone is aware that it's not that easy to define.
8. What's the working mechanism of CAR-T cell therapy?
Yeah, I think that question we already covered. You will target an antigen on the tumor cell on the outer surface. And then once the T-cell is connected, so the receptor, it triggers the T-cell also to expand like the normal immune response and you will have that standard machinery. So you will destroy the tumor cells. You have cytokine effects, etc. You use your own immune system, that machinery. The only thing with a CAR is that you can target a tumor cell. And then you use your own immune response.
9. What are the major challenges in CAR-T product manufacturing?
I think it's mainly due to the variety of starting materials. We treat very sick patients for which this treatment is maybe already their third line of treatment. So currently the CAR-T products are not first-in-line treatments. So it's for relapse, refractory patients in the third line. So they already have two other types of therapies that they’ve undergone. So the patient is very sick. Then also the collection, what you will collect, the quality of their T cells is varied. It depends also on how collection sites perform the activity. There are very variable starting products, and that's difficult to harmonize. So I think that's one of the major challenges during manufacturing. And of course, the supply chain is very complex, so you have very sick patients. It takes a long time to do all that harvesting and the expansion of cells. Sometimes, the patient needs to wait one month, maybe they don't even have that long to live and they die before they can receive the treatment. As a manufacturer, we need to improve so that we have shorter lead times, and that we can treat patients on time. So lead times are a challenge too.
10. How are CAR-T products stored? What are the difficulties in the supply chain?
Once collected in the hospital the cells need to be cryopreserved. They are cryopreserved within one day or two days after collection. So cryopreservation is maintaining the cells and then you will store them in vapor, liquid nitrogen at a temperature of minus 120 degrees or lower for stability. Also for the end product that's again needed, for stability and maintaining the T-cells’ capabilities.
Then you need to have that complex logging of temperatures, follow-up, specific equipment, storage, etc. It brings a lot of difficulties. Good distribution practices and good follow-up of the supply chain apply.
11. What are the major safety risks with CAR-T cell therapy?
I think the main safety risks are the neurological risks with CAR-Ts and also the cytokine release syndrome. And that's mainly on the basis of how T-cells cells work. So it'll destroy cells that will create a lot of cytokine reactions, and sometimes it's an overstimulation of the immune system. And then you can have those very severe cytokine release syndromes with fever etc. That's why hospital sites need to have that rescue medication on site. So that's specifically Tocilizumab. And that's also something that is mandatory by authorities, that they have four doses available per patient.
It was great to have you, Lieve! Your indispensable insights on these novel therapies will help steer us towards the Smart Quality future.
If you’re looking for an agile software platform tailored for ATMPs with a powerful QMS, strict compliance, and Smart Quality baked in - look no further than Scilife!
