About ten years ago Fate Therapeutics began to look at iPSCs as a way to create new ways of strategies in regenerative medicine. With the founders, such as Rudolf Jaenisch who was one of the pioneers of induced pluripotent stem cell technology, we started thinking about how we were going to bring this really cool technology into the field of regenerative medicine. Around 2012 the CAR T field took off and we saw really nice synergy with the adoptive cell therapy that is going forward, combining that with iPSCs to make off-the-shelf products. That’s when we started having conversations with the pioneer of adoptive CAR-19 therapy, which is Michel Sadelain and that led us down this path.
The presentation really highlights the ability to make an off-the-shelf CAR-T product from a master cell bank. Traditionally autologous strategies start with the patient’s material, patient’s cells that are selected for T-cells and engineered. That’s a great start but cancer patients’ T-cells are already exhausted, they’re impaired and this process is actually very long and has a lot of steps that are challenging. So, basically, what we wanted to do is how can we overcome these challenges by creating a master cell line that can basically produce the same material time and time for a large number of patients.
What challenges did this involve?
For autologous CAR-T therapy it works. Patients are really benefitting, those with B-cell lymphoma and leukaemia are really benefitting from this really novel, remarkably amazing product. But to go from the patient back to the patient with the new modified product you really have to go through this series of steps. One thing we’re starting to hear about is the apheresis, it’s just the starting material, is challenging because a lot of people are now trying to get this process going, the transplant folks and the CAR-T folks, they’re all trying to find their way into these sites, these processing sites. So just to get the material is challenging.
When you get the material then you’ve got to ship it off to the process centre. The process centre will do its thing, will hopefully be able to take these T-cells, culture them, because you have to culture, you have to engineer and they are able to basically go through this really long process of making the product and then sending it back. Then you start hearing stories about the product was made but unfortunately the patient passed away because they didn’t have this duration. Or you start hearing things about the cost, because the process is very expensive the costs get in the way for patient accessibility. And also the whole process usually for this is one dose. So now, say, it really worked well but you need a second dose and you’ve got to go through this whole process again.
So really the variability that comes into this process, because each patient is different, each T-cell is different, the cost, the logistics, it really makes it challenging to make this into a broad application. Eventually you want it to be like aspirin where you take one every four hours until your headache goes away or, in this case, until your cancer goes away.
That’s the ultimate dream and that’s what we’re trying to address because we’re not reinventing CAR-T, we’re just creating a platform, a cellular platform where you can now have it off the shelf accessible to every patient at a cost that’s affordable and you can also do multi-dosing.
So I really tried to address all those challenges that may slow down this remarkable discovery from being implemented to the entire cancer community.
How do you make the initial iPSC?
iPSCs are a very interesting cell type. Really it’s amazing to think about what they are, they’re cells that are kept in a petri dish and at any point you can differentiate them into any cell type. Sometimes you take it for granted when you’re working with them but it’s a petri dish of an embryonic like cell and after three weeks you have a hepatocyte or you have a blood cell. So they have this amazing ability to continuously maintain their embryonic like status but at the time of differentiation they can become the cell type based on your protocol, based on your interest of differentiation.
They also give you this ability to engineer them at the single cell level. Because of our technology we can take a single iPSC, put in all the attributes we want and then, because they can self-renew in an unlimited manner, expand them in a petri dish. Most primary cells get exhausted, you can’t start a T-cell from a single cell and expand it into 1e11, by that time the cell is exhausted and you don’t have an efficacious product. We overcome that by just taking the iPSC that’s been engineered at the single cell level and expand it into this large bank of iPSCs. Then we’ll take a vial from there, then we’ll differentiate into T-cells. So really we don’t make T-cells until the final few weeks so we don’t have an exhausted cell. We leverage the ability to go from an edited iPSC to an edited CD34 to an edited T-cell. Even though our process is forty days, for example, during the expansion and differentiation we really don’t work with T-cells towards the end. But once we have the T-cells the product is pure and is the same product every time we do this. So you end up with this almost unlimited bank of cells that you can tap into every time you start from the iPSC.
How does the turnover and dosage amount relate?
Dosing, the number of doses we make depends on the dosing of the patient. There are many dose escalations that we will conduct during the initial clinical trials. So our expectation is that the dose will be somewhere between 1e6 to 1e9 cells per patient. If that is going to be, which I believe will be the case, then for each run we make about 1e11, 1e12 cells with our current manufacturing process. So those are hundreds to thousands of doses that you have now per a forty day process.
The beauty of this process is that you are not limited by this number of cells, you’re limited by the vessel. So if you end up being able to create a larger volume then you can make more cells. When we think about show cells that are used to make monoclonal antibodies they get dumped into 15,000 litre bioreactors. If we’re able to get there eventually then you could almost imagine you’re making 1e13 cells and if you’re making 1e13 cells then you’re in a good place because you’re not going to run out. Just that one vial is going to give you enough cells for years to come. But say it runs out, you still go back to the same starting material, same process and make those doses again.
How will that process affect cost?
It’s quite remarkable in terms of when you do the math, a process like that ends up getting divided by the thousands of doses and ends up being magnitudes less than the current $500,000 tag price. So I don’t want to give a number because we haven’t done this but it will be significantly less. I don’t mean we go from 500 to 50, I think you go one more click less. So it will be possible to pretend it’s aspirin and take it once a month until the cancer goes. The economics are going to make that possible; the availability of the cells and the economics of the price should make multi-dosing feasible. And I think you’re going to need that for cancer. As cancer evolves you have to continuously come in with fresh cells to attack it, just like how your body on a daily basis makes NK and T-cells to regulate all the transformations that are occurring in your body. I think you have to come in with a renewable source as well.
When will this become a reality?
That’s a great question. Our first product is an NK cell, so we are making NK cells today for adoptive cell therapy, adoptive cancer immunotherapy, and that’s in the IND phase. So we hope that by the end of the year we are treating patients with NK cells. I feel that the T-cells are just one year behind. So in the same place where the NK cells were last year and we’re now in the IND stage I think the T-cells will next year be at the IND stage as well. So we hope that by the end of next year we’re dosing patients. It’s hard to predict some of these things but working with MSKCC and their breadth of knowledge when it comes to CAR-T therapy and GNP manufacturing you get a little more confidence that you might actually be able to achieve this goal.
Anything to add?
Autologous CAR-T works really well, I don’t want to suggest it doesn’t. It’s just it needs to evolve into a process where now it can be amenable to everybody and not just select people who are close to a certain hospital. And cost should not get in the way of treatment. So we hope that we can take this remarkable discovery that several pioneers have brought to the clinic and just make it more amenable to the general audience, the general cancer patients.